Human glucagon-like peptide-1 mimics and their use in the treatment of diabetes and related conditions

ABSTRACT

The present invention provides novel human glucagon-like peptide-1 (GLP-1) peptide mimics that mimic the biological activity of the native GLP-1 peptide and thus are useful for the treatment or prevention of diseases or disorders associated with GLP activity. Further, the present invention provides novel, chemically modified peptides that not only stimulate insulin secretion in type II diabetics, but also produce other beneficial insulinotropic responses. These synthetic peptide GLP-1 mimics exhibit increased stability to proteolytic cleavage making them ideal therapeutic candidates for oral or parenteral administration.

This application is a divisional of U.S. application Ser. No.10/273,975, filed Oct. 18, 2002, which claims the benefit of U.S.Provisional Application Ser. No. 60/342,015, filed Oct. 18, 2001. Eachof the priority applications are incorporated by reference in theirentireties.

FIELD OF THE INVENTION

The present invention provides novel human glucagon-like peptide-1(GLP-1) peptide mimics, which duplicate the biological activity of thenative peptide, exhibit increased stability to proteolytic cleavage ascompared to GLP-1 native sequences, and thus are useful for theamelioration of the diabetic condition.

BACKGROUND OF THE INVENTION

GLP-1 is an important gut hormone with regulatory function in glucosemetabolism and gastrointestinal secretion and metabolism. Human GLP-1 isa 30 amino acid residue peptide originating from preproglucagon, whichis synthesized for example, in the L-cells in the distal ileum, in thepancreas and in the brain. Processing of preproglucagon to yield GLP-1(7-36) amide and GLP-2 occurs mainly in the L-cells. GLP-1 is normallysecreted in response to food intake; in particular carbohydrates andlipids stimulate GLP-1 secretion. GLP-1 has been identified as a verypotent and efficacious stimulator for insulin release. GLP-1 lowersglucagon concentration, slows gastric emptying, stimulates insulinbiosynthesis and enhances insulin sensitivity (Nauck, 1997, Horm. Metab.Res. 47:1253-1258). GLP-1 also enhances the ability of the B-cells tosense and respond to glucose in subjects with impaired glucose tolerance(Byrne, Eur. J. Clin. Invest., 28:72-78, 1998). The insulinotropiceffect of GLP-1 in humans increases the rate of glucose metabolismpartly due to increased insulin levels and partly due to enhancedinsulin sensitivity (D'Alessio, Eur. J. Clin. Invest., 28:72-78, 1994).The above stated pharmacological properties of GLP-1 make it a highlydesirable therapeutic agent for the treatment of type-II diabetes.Additionally, recent studies have shown that infusions of slightlysupraphysiological amounts of GLP-1 significantly enhance satiety andreduce food intake in normal subjects (Flint, A., Raben, A., Astrup, A.and Holst, J. J., J. Clin. Invest, 101:515-520, 1998; Gutswiller, J. P.,Goke, B., Drewe, J., Hildebrand, P., Ketterer, S., Handschin, D.,Winterhaider, R., Conen, D and Beglinger, C., Gut, 44:81-86, 1999;). Theeffect on food intake and satiety has also been reported to be preservedin obese subjects (Naslund, E., Barkeling, B., King, N., Gutniak, M.,Blundell, J. E., Holst, J. J., Rossner, S., and Hellstrom, P. M., Int.J. Obes. Relat. Metab. Disord., 23:304-311, 1999). In the above-citedstudies a pronounced effect of GLP-1 on gastric emptying was alsosuspected to occur. Gastric emptying results in post-prandial glucoseexcursions. It has also been shown that in addition to stimulation ofinsulin secretion, GLP-1 stimulates the expression of the transcriptionfactor IDX-1 while stimulating B-cell neogenesis and may thereby be aneffective treatment and/or preventive agent for diabetes (Stoffers, D.A., Kieffer, T. J. Hussain, M. A., Drucker, D. J., Bonner-Weir, S.,Habener, J. F. and Egan, J. M. Diabetes, 40:741-748, 2000). GLP-1 hasalso been shown to inhibit gastric acid secretion (Wettergren, A.,Schjoldager, B., Mortensen, P. E., Myhre, J., Christiansen, J., andHolst, J. J., Dig. Dis. Sci., 38:665-673, 1993), which may provideprotection against gastric ulcers.

GLP-1 is an incretin hormone, for example, an intestinal hormone thatenhances meal-induced insulin secretion (Holst, J. J., Curr. Med. Chem.,6:1005-1017, 1999). It is a product of the glucagon gene encodingproglucagon. This gene is expressed not only in the A-cells of thepancreas but also in the endocrine L-cells of the intestinal mucosa.Proglucagon is a peptide (protein) containing 160 amino acids. Furtherprocessing of proglucagon results in the generation of a) glucagon, b)an N-terminal, presumably inactive fragment, and c) a large C-terminalfragment commonly referred as “the major proglucagon fragment”. Thisfragment is considered to be biologically inactive. Even though thisfragment is present in both pancreas and in the L-cells of the gut, itis only in the intestines the breakdown products of the “the majorproglucagon fragment” resulting in two highly homologous peptidescommonly referred as GLP-1 and GLP-2 are observed. These two peptideshave important biological activities. As such, the amino acid sequenceof GLP-1, which is present in the L-cells, is identical to the 78-107portion of proglucagon.

The present invention provides novel GLP-1 peptide mimics that duplicatethe biological activity of the native peptide and thus are useful forthe amelioration of the diabetic condition.

Presently, therapy involving the use of GLP-1-type molecules haspresented a significant problem because the serum half-life of suchpeptides is quite short. For example, GLP-1 (7-37) has a serum half-lifeof only 3 to 5 minutes. Thus there exists a critical need forbiologically active GLP-1 mimics that possess extended pharmacodynamicprofiles.

SUMMARY OF THE INVENTION

In accordance with the present invention, synthetic isolatedpolypeptides are provided which have the structure of Formula IA-X_(aa1)-X_(aa2)-X_(aa3)-X_(aa4)-X_(aa5)-X_(aa6)-X_(aa7)-X_(aa8)-X_(aa9)-Y-Z-B  I

wherein,

X_(aa1-9) is a naturally or nonnaturally occurring amino acid residue;

Y and Z are amino acid residues;

wherein one of the substitutions at the alpha-carbon atoms of Y and Zmay each independently be substituted with a primary substituent groupselected from the group consisting of hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl,heterocyclylalkyl said primary substituent optionally being substitutedwith a secondary substituent selected from a cycloalkyl, heterocyclyl,aryl or heteroaryl group; any of said primary or secondary substituentsmay further be substituted with one or more of, hydrogen, alkyl,cycloalkyl, arylalkyl, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl,halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido,guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl,acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy,heterocycleoxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl,mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl,guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl orphosphonic group; wherein, the primary or secondary substitutents mayoptionally be bridged by covalent bonds to form one or more fused cyclicor heterocyclic systems with each other;

wherein, the other substitution at the alpha-carbon of Y may besubstituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl orcarboxyalkyl;

wherein, the other substitution at the alpha-carbon of Z may besubstituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl orcarboxyalkyl;

A and B are optionally present;

wherein A is present and A is hydrogen, an amino acid or peptidecontaining from about 1 to about 15 amino acid residues, an R group, anR—C(O) (amide) group, a carbamate group RO—C(O), a urea R₄R₅N—C(O), asulfonamido R—SO₂, or a R₄R₅N—SO₂;

wherein R is selected from the group consisting of hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl,heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl andheteroaryloxyalkyl;

wherein R₄ and R₅ are each independently selected from the groupconsisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl,aryloxyalkyl, heteroarylalkyl and heteroaryloxyalky;

wherein the alpha-amino group of X_(aa1) is substituted with a hydrogenor an alkyl group, said alkyl group may optionally form a ring with A;

wherein B is present and B is OR₁, NR₁R₂, or an amino acid or peptidecontaining from 1 to 15 amino acid residues, preferably 1 to 10, morepreferably 1 to 5 terminating at the C-terminus as a carboxamide,substituted carboxamide, an ester, a free carboxylic acid or anamino-alcohol;

wherein R₁ and R₂ are independently chosen from hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl,heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl orheteroaryloxyalkyl.

Preferred substitutions upon the alpha-carbon atoms of Y and Z areselected from the group consisting of heteroarylarylmethyl,arylheteroarylmethyl or biphenylmethyl forming biphenylalanine residues,any of which is also optionally substituted with one or more, hydrogen,alkyl, cycloalkyl, arylalkyl, aryl, heterocyclyl, heteroaryl, alkenyl,alkynyl, halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido,guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl,acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy,heterocycleoxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl,mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl,guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl andphosphonic group.

Further embodiments include isolated polypeptides wherein the othersubstitution at the alpha-carbon of Y is substituted with hydrogen,methyl or ethyl; and wherein, the other substitution at the alpha-carbonof Z is substituted with hydrogen, methyl or ethyl.

Further embodiments include isolated polypeptides as described abovewherein

X_(aa1) is naturally or nonnaturally occurring amino acid residue inwhich one of the substitutions at the alpha-carbon is a primarysubstituent selected from the group consisting of heterocyclylalkyl,heteroaryl, heteroarylalkyl and arylalkyl, said primary substituentoptionally being substituted with secondary substituent selected fromheteroaryl or heterocyclyl; and in which the other substitution at thealpha-carbon is hydrogen or alkyl;

X_(aa2) is naturally or nonnaturally occurring amino acid residue inwhich one of the substitutions at the alpha-carbon is an alkyl orcycloalkyl where the alkyl group may optionally form a ring with thenitrogen of X_(aa2); and wherein the other substitution at thealpha-carbon is hydrogen or alkyl;

X_(aa3) is a naturally or nonnaturally occurring amino acid residue inwhich one of the substitutions at the alpha-carbon is selected from thegroup consisting of a carboxyalkyl, bis-carboxyalkyl, sulfonylalkyl,heteroalkyl and mercaptoalkyl; and wherein the other substitution at thealpha-carbon is hydrogen or alkyl;

X_(aa4) is a naturally or nonnaturally occurring amino acid residue inwhich the alpha-carbon is not substituted, or in which one of thesubstitutions at the alpha-carbon is selected from the group consistingof aminoalkyl, carboxyalkyl heteroarylalkyl and heterocycylalkyl;

X_(aa5) is a naturally or nonnaturally occurring amino acid residue inwhich one of the substitutions at the alpha-carbon is an alkyl orhydroxyalkyl, and in which the other substitution at the alpha-carbon ishydrogen or alkyl;

X_(aa6) is a naturally or nonnaturally occurring amino acid residue inwhich one of the substitutions at the alpha-carbon is selected from thegroup consisting of alkyl, aryl, heteroaryl, heterocyclyl,cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl group,and wherein the other substitution at the alpha-carbon is hydrogen oralkyl;

X_(aa7) is a naturally or nonnaturally occurring amino acid residue inwhich one of the substitutions at the alpha-carbon is a hydroxylalkylgroup;

X_(aa8) is a naturally or nonnaturally occurring amino acid residue inwhich one of the substitutions at the alpha-carbon is selected from thegroup consisting of alkyl, hydroxylalkyl, heteroarylalkyl andcarboxamidoalkyl, and in which the other substitution at thealpha-carbon is hydrogen or alkyl;

X_(aa9) is a naturally or nonnaturally occurring amino acid residue inwhich one of the substitutions at alpha-carbon is selected from thegroup consisting of carboxylalkyl, bis-carboxylalkyl, carboxylaryl,sulfonylalkyl, carboxylamidoalkyl and heteroarylalkyl; and wherein

A is hydrogen, an amino acid or peptide containing from about 1 to aboutamino acid residues, an R group, an R—C(O) amide group, a carbamategroup RO—C(O), a urea R₄R₅N—C(O), a sulfonamido R—SO₂ or a R₄R₅N—SO₂.

Preferred are isolated peptides wherein

X_(aa1) is an amino acid residue selected from the group consisting ofL-His, D-His, L-N-Methyl-His, D-N-Methyl-His, L-4-ThiazolylAla andD-4-ThiazolylAla;

X_(aa2) is an amino acid residue selected from the group consisting ofL-Ala, D-Ala, L-Pro, Gly, D-Ser, D-Asn, L-N-Methyl-Ala, D-N-Methyl-Ala,L-4-ThioPro, L-Pro(t-4-OH) (“L-4-hydroxyproline”), L-2-Pip, L-2-Azt,Aib, S- or R-Iva and Acc₃;

X_(aa3) is an amino acid residue selected from the group consisting ofL-Glu, L-N-Methyl-Glu, L-Asp, D-Asp, L-His, L-Gla, L-Adp, L-Cys andL-4-ThiazolylAla;

X_(aa4) is an amino acid residue selected from the group consisting ofGly, L-His, L-Lys and L-Asp;

X_(aa5) is an amino acid residue selected from the group consisting ofL-Thr, D-Thr, L-Nle, L-Met, L-Nva and L-Aoc;

X_(aa6) is an amino acid residue selected from the group consisting ofL-Phe, L-Tyr, L-Tyr(Bzl), Tyr(3-NO₂), L-Nle, L-Trp, L-Phe(penta-Fluoro),D-Phe(penta-Fluoro), Phe(2-Fluoro), Phe(3-Fluoro), Phe(4-Fluoro),Phe(2,3-di-Fluoro), Phe(3,4-di-Fluoro), Phe(3,5-di-Fluoro),L-Phe(2,6-di-Fluoro), Phe(3,4,5-tri-Fluoro), Phe(2-Iodo), Phe(2-OH),Phe(2-OMethyl), Phe(3-OMethyl), Phe(3-Cyano), Phe(2-Chloro), Phe(2-NH₂),Phe(3-NH₂), Phe(4-NH₂), Phe(4-NO₂), Phe(4-Methyl), Phe(4-Allyl),Phe(n-butyl), Phe(4-Cyclohexyl), Phe(4-Cyclohexyloxy), Phe(4-Phenyloxy),2-NaphthylAla, 2-PyridylAla, L-4-ThiazolylAla, L-2-Thi, L-α-Me-Phe,D-α-Me-Phe, L-α-Et-Phe, D-α-Et-Phe, L-α-Me-Phe(2-Fluoro),D-α-Me-Phe(2-Fluoro), L-α-Me-Phe(2,3-di-Fluoro),D-α-Me-Phe(2,3-di-Fluoro), L-α-Me-Phe(2,6-di-Fluoro),D-α-Me-Phe(2,6-di-Fluoro), L-α-Me-Phe(penta-Fluoro) andD-α-Me-Phe(penta-Fluoro);

X_(aa7) is an amino acid residue selected from the group consisting ofL-Thr, D-Thr, L-Ser and L-hSer;

X_(aa8) is an amino acid residue selected from the group consisting ofL-Ser, L-hSer, L-His, L-Asn and L-α-Me-Ser; and

X_(aa9) is an amino acid residue selected from the group consisting ofL-Asp, L-Glu, L-Gla, L-Adp, L-Asn and L-His.

Additional embodiments include those wherein

Y is selected from the group consisting of L-Bip, D-Bip, L-Bip(2-Me),D-Bip(2-Me), L-Bip(2′-Me), L-Bip(2-Et), D-Bip(2-Et), L-Bip(3-Et),L-Bip(4-Et), L-Bip(2-n-Propyl), L-Bip(2-n-Propyl, 4-OMe),L-Bip(2-n-Propyl,2′-Me), L-Bip(3-Me), L-Bip(4-Me), L-Bip(2,3-di-Me),L-Bip(2,4-di-Me), L-Bip(2,6-di-Me), L-Bip(2,4-di-Et), L-Bip(2-Me,2′-Me), L-Bip(2-Et, 2′-Me), L-Bip(2-Et, 2′-Et), L-Bip(2-Me,4-OMe),L-Bip(2-Et,4-OMe), D-Bip(2-Et,4-OMe), L-Bip(3-OMe), L-Bip(4-OMe),L-Bip(2,4,6-tri-Me), L-Bip(2,3-di-OMe), L-Bip(2,4-di-OMe),L-Bip(2,5-di-OMe), L-Bip(3,4-di-OMe), L-Bip(2-Et,4,5-di-OMe),L-Bip(3,4-Methylene-di-oxy), L-Bip(2-Et, 4,5-Methylene-di-oxy),L-Bip(2-CH₂OH, 4-OMe), L-Bip(2-Ac), L-Bip(3-NH-Ac), L-Bip(4-NH-Ac),L-Bip(2,3-di-Chloro), L-Bip(2,4-di-Chloro), L-Bip(2,5-di-Chloro),L-Bip(3,4-di-Chloro), L-Bip(4-Fluoro), L-Bip(3,4-di-Fluoro),L-Bip(2,5-di-Fluoro), L-Bip(3-n-Propyl), L-Bip(4-n-Propyl),L-Bip(2-iso-Propyl), L-Bip(3-iso-Propyl), L-Bip(4-iso-Propyl),L-Bip(4-tert-Butyl), L-Bip(3-Phenyl), L-Bip(2-Chloro), L-Bip(3-Chloro),L-Bip(2-Fluoro), L-Bip(3-Fluoro), L-Bip(2-CF₃), L-Bip(3-CF₃),L-Bip(4-CF₃), L-Bip(3-NO₂), L-Bip(3-OCF₃), L-Bip(4-OCF₃), L-Bip(2-OEt),L-Bip(3-OEt), L-Bip(4-OEt), L-Bip(4-SMe), L-Bip(2-OH), L-Bip(3-OH),L-Bip(4-OH), L-Bip(2-CH₂—COOH), L-Bip(3-CH₂—COOH), L-Bip(4-CH₂—COOH),L-Bip(2-CH₂—NH₂), L-Bip(3-CH₂—NH₂), L-Bip(4-CH₂—NH₂), L-Bip(2-CH₂—OH),L-Bip(3-CH₂—OH), L-Bip(4-CH₂—OH), L-Phe[4-(1-propargyl)],L-Phe[4-(1-propenyl)], L-Phe[4-n-Butyl], L-Phe[4-Cyclohexyl],Phe(4-Phenyloxy), L-Phe(penta-Fluoro),L-2-(9,10-Dihydrophenanthrenyl)-Ala, 4-(2-Benzo(b)furan)-Phe,4-(4-Dibenzofuran)-Phe, 4-(4-Phenoxathiin)-Phe,4-(2-Benzo(b)thiophene)-Phe, 4-(3-thiophene)-Phe, 4-(3-Quinoline)-Phe,4-(2-Naphthyl)-Phe, 4-(1-Naphthyl)-Phe,4-(4-(3,5-dimethylisoxazole))-Phe, 4-(2,4-dimethoxypyrimidine)-Phe,homoPhe, Tyr(Bzl), Phe(3,4-di-Chloro), Phe(4-Iodo), 2-Naphthyl-Ala,L-α-Me-Bip and D-α-Me-Bip;

Z is selected from the group consisting of L-Bip, D-Bip, L-Bip(2-Me),D-Bip(2-Me), L-Bip(2′-Me), L-Bip(2-Et), D-Bip(2-Et), L-Bip(3-Me),L-Bip(4-Me), L-Bip(3-OMe), L-Bip(4-OMe), L-Bip(4-Et),L-Bip(2-n-Propyl,2′-Me), L-Bip(2,4-di-Me), L-Bip(2-Me, 2′-Me),L-Bip(2-Me,4-OMe), L-Bip(2-Et,4-OMe), D-Bip(2-Et,4-OMe),L-Bip(2,6-di-Me), L-Bip(2,4,6-tri-Me), L-Bip(2,3,4,5,-tetra-Me),L-Bip(3,4-di-OMe), L-Bip(2,5-di-OMe), L-Bip(3,4-Methylene-di-oxy),L-Bip(3-NH-Ac), L-Bip(2-iso-Propyl), L-Bip(4-iso-Propyl),L-Bip(2-Phenyl), L-Bip(4-Phenyl), L-Bip(2-Fluoro), L-Bip(4-CF₃),L-Bip(4-OCF₃), L-Bip(2-OEt), L-Bip(4-OEt), L-Bip(4-SMe),L-Bip(2-CH₂—COOH), D-Bip(2-CH₂—COOH), L-Bip(2′-CH₂—COOH),L-Bip(3-CH₂—COOH), L-Bip(4-CH₂—COOH), L-Bip(2-CH₂—NH₂),L-Bip(3-CH₂—NH₂), L-Bip(4-CH₂—NH₂), L-Bip(2-CH₂—OH), L-Bip(3-CH₂—OH),L-Bip(4-CH₂—OH), L-Phe(3-Phenyl), L-Phe[4-n-Butyl], L-Phe[4-Cyclohexyl],Phe(4-Phenyloxy), L-Phe(penta-Fluoro),L-2-(9,10-Dihydrophenanthrenyl)-Ala, 4-(3-Pyridyl)-Phe,4-(2-Naphthyl)-Phe, 4-(1-Naphthyl)-Phe, 2-Naphthyl-Ala, 2-Fluorenyl-Ala,L-α-Me-Bip, D-α-Me-Bip, L-Phe(4-NO₂) and L-Phe(4-Iodo);

A is selected from the group consisting of H, Acetyl, β-Ala, Ahx, Gly,Asp, Glu, Phe, Lys, Nva, Asn, Arg, Ser, Thr, Val, Trp, Tyr, Caprolactam,L-Bip, L-Ser(Bzl), 3-PyridylAla, Phe(4-Me), Phe(penta-Fluoro),4-Methylbenzyl, 4-Fluorobenzyl, n-propyl, n-hexyl, cyclohexylmethyl,6-hydroxypentyl, 2-Thienylmethyl, 3-Thienylmethyl, penta-Fluorobenzyl,2-naphthylmethyl, 4-biphenylmethyl, 9-Anthracenylmethyl, benzyl,(S)-(2-amino-3-phenyl)propyl, methyl, 2-aminoethyl and(S)-2-Aminopropyl; and

B is selected from the group consisting of OH, NH₂, Trp-NH₂,2-NaphthylAla-NH₂, Phe(penta-Fluoro)-NH₂, Ser(Bzl)-NH₂, Phe(4-NO₂)—NH₂,3-PyridylAla-NH₂, Nva-NH₂, Lys-NH₂, Asp-NH₂, Ser-NH₂, His-NH₂, Tyr-NH₂,Phe-NH₂, L-Bip-NH₂, D-Ser-NH₂, Gly-OH, β-Ala-OH, GABA-OH and APA-OH.

When A is not present, and X_(aa1) is an R group, an R—C(O) (amide)group, a carbamate group RO—C(O), a urea R₄R₅N—C(O), a sulfonamidoR—SO₂, or a R₄R₅N—SO₂; wherein

R is selected from the group consisting of hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl,arylalkyl, aryloxyalkyl, heteroarylalkyl, heteroaryloxyalkyl andheteroarylalkoxyalkyl; and wherein

R₄ and R₅ are each independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl,heteroarylalkyl and heteroaryloxyalkyl.

When B is not present and Z is OR₁, NR₁R₂ or an amino-alcohol; wherein

R₁ and R₂ are independently chosen from hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, heteroaryl,arylalkyl, aryloxyalkyl, heteroarylalkyl or heteroaryloxyalkyl.

Preferred are isolated polypeptides wherein X_(aa1) (where applicable),X_(aa2) and X_(aa3) are N—H or N-alkylated, preferably N-methylatedamino acid residues.

Preferably the isolated polypeptide is a 10-mer to 15-mer and suchpolypeptide and binds to and activates the GLP-1 receptor.

The present invention also provides a method of making a polypeptidethat mimics the activity of a polypeptide receptor agonist.

In accordance with the present invention, the synthetic isolatedpeptides described herein possess the ability to mimic the biologicalactivity of GLP peptides, with preference for mimicking GLP-1. Thesesynthetic peptide GLP-1 mimics exhibit desirable in-vivo properties,thus making them ideal therapeutic candidates for oral or parenteraladministration.

The present invention also provides an isolated polypeptide according toFormula 1, wherein the polypeptide is a Glucagon-Like-Peptidederivative, preferably a Glucagon-Like-Peptide-1 derivative.

The present invention provides for polypeptides of formula I,pharmaceutical compositions employing such polypeptides and for methodsof using such polypeptides. In particular, the present inventionprovides a pharmaceutical composition comprising a therapeuticallyeffective amount of a polypeptide of formula I, alone or in combinationwith a pharmaceutically acceptable carrier.

Further provided is a method for treating or delaying the progression oronset of diabetes, especially type II diabetes, including complicationsof diabetes, including retinopathy, neuropathy, nephropathy and delayedwound healing, and related diseases such as insulin resistance (impairedglucose homeostasis), hyperglycemia, hyperinsulinemia, elevated bloodlevels of fatty acids or glycerol, obesity, hyperlipidemia includinghypertriglyceridemia, Syndrome X, atherosclerosis and hypertension, andfor increasing high density lipoprotein levels, wherein atherapeutically effective amount of a polypeptide of formula I isadministered to a mammalian, e.g., human, patient in need of treatment.

The polypeptides of the invention can be used alone, in combination withother polypeptides of the present invention, or in combination with oneor more other agent(s) active in the therapeutic areas described herein.

In addition, a method is provided for treating diabetes and relateddiseases as defined above and hereinafter, wherein a therapeuticallyeffective amount of a combination of a polypeptide of formula I and atleast one other type of therapeutic agent, such as an antidiabeticagent, a hypolipidemic agent or anti-obesity agent, is administered to ahuman patient in need of treatment.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the effects of intravenous infusion of Compound A andGLP-1 on plasma glucose in scGTT in rats.

FIG. 2 illustrates the effects of intravenous infusion of Compound B andGLP-1 on plasma glucose in scGT in rats.

FIG. 3 illustrates the effects of subcutaneous injection of Compound Aand GLP-1 on plasma glucose in scGTT in rats.

FIG. 4 illustrates the effects of subcutaneous injection of Compound Band GLP-1 on plasma glucose in scGTT in rats.

FIG. 5 illustrates the effects of subcutaneous injection of Compound Con plasma glucose in an ipGTT model in rats.

FIG. 6 illustrates the effects of subcutaneous injection of Compound Don plasma glucose in an ipGTT model in rats.

FIG. 7 illustrates the effects of subcutaneous injection of GLP-1 onplasma glucose in an ipGTT model in rats.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions apply to the terms as used throughout thisspecification, unless otherwise limited in specific instances.

Unless otherwise indicated, the term “amino-alcohol” as employed hereinalone or as part of another group includes a natural or un-natural aminoacid in which the carboxy group is replaced (reduced) to a methylalcohol such as valinol, glycinol, alaminol, arylalaminol,heteroarylalaminol.

Unless otherwise indicated, the term “alkyl” as employed herein alone oras part of another group includes both straight and branched chainhydrocarbons, containing 1 to 40 carbons, preferably 1 to 20 carbons,more preferably 1 to 8 carbons, in the normal chain, such as methyl,ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl,isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl,nonyl, decyl, undecyl, dodecyl, the various branched chain isomersthereof, and the like. Further, alkyl groups, as defined herein, mayoptionally be substituted on any available carbon atom with one or morefunctional groups commonly attached to such chains, such as, but notlimited to alkyl, aryl, alkenyl, alkynyl, hydroxy, arylalkyl,cycloalkyl, cycloalkylalkyl, alkoxy, arylalkyloxy, heteroaryloxy,heteroarylalkyloxy, alkanoyl, halo, hydroxyl, thio, nitro, cyano,carboxyl, carbonyl (

), carboxamido, amino, alkylamino, dialkylamino, amido, alkylamino,arylamido, heterarylamido, azido, guanidino, amidino, phosphonic,phosphinic, sulfonic, sulfonamido, haloaryl, CF₃, OCF₂, OCF₃, aryloxy,heteroaryl, cycloalkylalkoxyalkyl, cycloheteroalkyl and the like to formalkyl groups such as trifluoro methyl, 3-hydroxyhexyl, 2-carboxypropyl,2-fluoroethyl, carboxymethyl, cyanobutyl and the like.

Unless otherwise indicated, the term “alkenyl” as employed herein aloneor as part of another group includes both straight and branched chainhydrocarbons, containing 2 to 40 carbons with one or more double bonds,preferably 2 to 20 carbons with one to three double bonds, morepreferably 2 to 8 carbons with one to two double bonds, in the normalchain, such that any carbon may be optionally substituted as describedabove for “alkyl”.

Unless otherwise indicated, the term “alkynyl” as employed herein aloneor as part of another group includes both straight and branched chainhydrocarbons, containing 2 to 40 carbons with one or more triple bonds,preferably 2 to 20 carbons with one to three triple bonds, morepreferably 2 to 8 carbons with one to two triple bonds, in the normalchain, such that any carbon may be optionally substituted as describedabove for “alkyl”.

Unless otherwise indicated, the term “cycloalkyl” as employed hereinalone or as part of another group includes saturated or partiallyunsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groupscontaining 1 to 3 rings, appended or fused, including monocyclic alkyl,bicyclic alkyl and tricyclic alkyl, containing a total of 3 to 20carbons forming the rings, preferably 4 to 7 carbons, forming each ring;which may be fused to 1 aromatic ring as described for aryl, whichinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclodecyl, cyclododecyl, cyclohexenyl,

any of which groups may be optionally substituted through any availablecarbon atoms with 1 or more groups selected from hydrogen, halo,haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl,trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkylalkyl, fluorenyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl,aryloxy, aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl,heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro,oxo, cyano, carboxyl, carbonyl (

), carboxamido, amino, substituted amino wherein the amino includes 1 or2 substituents (which are alkyl, aryl or any of the other aryl compoundsmentioned in the definitions), amido, azido, guanidino, amidino,phosphonic, phosphinic, sulfonic, sulfonamido, thiol, alkylthio,arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl,arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl,aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino,arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino orarylsulfonaminocarbonyl, or any of alkyl substituents as set out above.

The term “aryl” as employed herein alone or as part of another grouprefers to monocyclic and bicyclic aromatic groups containing 6 to 10carbons in the ring portion (such as phenyl or naphthyl) and mayoptionally include one to three additional rings fused to “aryl” (suchas aryl, cycloalkyl, heteroaryl or heterocycloalkyl rings) and may beoptionally substituted through any available carbon atoms with 1 or moregroups selected from hydrogen, alkyl, halo, haloalkyl, alkoxy,haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl,cycloalkylalkyl, fluorenyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy,arylthio, arylazo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy,hetroarylalkyloxy, hetroarylalkyloxyalkyl, hydroxy, nitro, oxo, cyano,amino, substituted amino wherein the amino includes 1 or 2 substituents(which are alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl orany of the other aryl compounds mentioned in the definitions), thiol,alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio,alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl,cycloalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl,heteroarylalkylaminocarbonyl alkoxycarbonyl, aminocarbonyl,alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino,arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino orarylsulfonaminocarbonyl, or any of alkyl substituents as set out above.

The term “arylalkyl” as used herein alone or as part of another grouprefers to alkyl groups as defined above having an aryl substituent, suchas benzyl, phenethyl or naphthylpropyl, wherein said aryl and/or alkylgroups may optionally be substituted as defined above.

The term “alkoxy”, “aryloxy”, “heteroaryloxy” “arylalkyloxy”, or“heteroarylalkyloxy” as employed herein alone or as part of anothergroup includes an alkyl or aryl group as defined above linked through anoxygen atom.

The term “heterocyclo”, “heterocycle” “heterocyclyl” or “heterocyclic”,as used herein, represents an unsubstituted or substituted stable 4-,5-, 6- or 7-membered monocyclic ring system which may be saturated orunsaturated, and which consists of carbon atoms and from one to fourheteroatoms selected from nitrogen, sulfur, oxygen and/or a SO or SO₂group, wherein the nitrogen and sulfur heteroatoms may optionally beoxidized, and the nitrogen heteroatom may optionally be quaternized. Theheterocyclic ring may be attached at any heteroatom or carbon atom whichresults in the creation of a stable structure. Examples of suchheterocyclic groups include, but are not limited to, tetrahydrofuranyl,tetrahydrothiophenyl pyrrolidinyl, piperidinyl, piperazinyl,oxopyrrolidinyl, oxopiperazinyl, oxopiperidinyl and oxadiazolyl.Optionally a heterocyclo group may be substituted with one or morefunctional groups, such as those described for “alkyl” or “aryl”.

The term “heterocycloalkyl” as used herein alone or as part of anothergroup refers to alkyl groups as defined above having a heterocycloalkylsubstituent, wherein said “heterocyclo” and/or alkyl groups mayoptionally be substituted as defined above.

The term “heteroaryl” as used herein refers to a 5-, 6- or 7-memberedaromatic heterocyclic ring which contains one or more heteroatomsselected from nitrogen, sulfur, oxygen and/or a SO or SO₂ group. Suchrings may be fused to another aryl or heteroaryl ring and includepossible N-oxides; Examples of such heteroaryl groups include, but arenot limited to, furan, pyrrole, thiophene, pyridine, isoxazole, oxazole,imidazole and the like. Optionally a heteroaryl group may be substitutedwith one or more functional groups commonly attached to such chains,such as those described for “alkyl” or “aryl”.

The term “heteroarylalkyl” as used herein alone or as part of anothergroup refers to alkyl groups as defined above having a heteroarylsubstituent, wherein said heteroaryl and/or alkyl groups may optionallybe substituted as defined above.

The term “diabetes and related diseases or related conditions” refers toType II diabetes, Type I diabetes, impaired glucose tolerance, obesity,hyperglycemia, Syndrome X, dysmetabolic syndrome, diabeticcomplications, and hyperinsulinemia.

The term “lipid-modulating” or “lipid lowering” agent as employed hereinrefers to agents that lower LDL and/or raise HDL and/or lowertriglycerides and/or lower total cholesterol and/or other knownmechanisms for therapeutically treating lipid disorders.

An administration of a therapeutic agent of the invention includesadministration of a therapeutically effective amount of the agent of theinvention. The term “therapeutically effective amount” as used hereinrefers to an amount of a therapeutic agent to treat or prevent acondition treatable by administration of a composition of the invention.That amount is the amount sufficient to exhibit a detectable therapeuticor preventative or ameliorative effect. The effect may include, forexample, treatment or prevention of the conditions listed herein. Theprecise effective amount for a subject will depend upon the subject'ssize and health, the nature and extent of the condition being treated,recommendations of the treating physician, and the therapeutics orcombination of therapeutics selected for administration. Thus, it is notuseful to specify an exact effective amount in advance.

The peptides and analogs thereof described herein may be produced bychemical synthesis using various solid-phase techniques such as thosedescribed in G. Barany and R. B. Merrifield, “The Peptides: Analysis,Synthesis, Biology”; Volume 2-“Special Methods in Peptide Synthesis,Part A”, pp. 3-284, E. Gross and J. Meienhofer, Eds., Academic Press,New York, 1980; and in J. M. Stewart and J. D. Young, “Solid-PhasePeptide Synthesis”, 2^(nd) Ed., Pierce Chemical Co., Rockford, Ill.,1984. The preferred strategy for use in this invention is based on theFmoc (9-Fluorenylmethylmethyloxycarbonyl) group for temporary protectionof the α-amino group, in combination with the tert-butyl group fortemporary protection of the amino acid side chains (see for example E.Atherton and R. C. Sheppard, “The Fluorenylmethoxycarbonyl AminoProtecting Group”, in “The Peptides: Analysis, Synthesis, Biology”;Volume 9—“Special Methods in Peptide Synthesis, Part C”, pp. 1-38, S.Undenfriend and J. Meienhofer, Eds., Academic Press, San Diego, 1987.

The peptides can be synthesized in a stepwise manner on an insolublepolymer support (also referred to as “resin”) starting from theC-terminus of the peptide. A synthesis is begun by appending theC-terminal amino acid of the peptide to the resin through formation ofan amide or ester linkage. This allows the eventual release of theresulting peptide as a C-terminal amide or carboxylic acid,respectively. Alternatively, in cases where a C-terminal amino alcoholis present, the C-terminal residue may be attached to2-Methoxy-4-alkoxybenzyl alcohol resin (SASRIN™, Bachem Bioscience,Inc., King of Prussia, Pa.) as described herein and, after completion ofthe peptide sequence assembly, the resulting peptide alcohol is releasedwith LiBH₄ in THF (see J. M. Stewart and J. D. Young, supra, p. 92).

The C-terminal amino acid and all other amino acids used in thesynthesis are required to have their α-amino groups and side chainfunctionalities (if present) differentially protected such that theα-amino protecting group may be selectively removed during thesynthesis. The coupling of an amino acid is performed by activation ofits carboxyl group as an active ester and reaction thereof with theunblocked α-amino group of the N-terminal amino acid appended to theresin. The sequence of α-amino group deprotection and coupling isrepeated until the entire peptide sequence is assembled. The peptide isthen released from the resin with concomitant deprotection of the sidechain functionalities, usually in the presence of appropriate scavengersto limit side reactions. The resulting peptide is finally purified byreverse phase HPLC.

The synthesis of the peptidyl-resins required as precursors to the finalpeptides utilizes commercially available cross-linked polystyrenepolymer resins (Novabiochem, San Diego, Calif.). Preferred for use inthis invention are4-(2′,4′-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetyl-p-methylbenzhydrylamine resin (Rink amide MBHA resin) or p-benzyloxybenzylalcohol resin (HMP resin) to which the C-terminal amino acid may or maynot be already attached. If the C-terminal amino acid is not attached,its attachment may be achieved by DMAP-catalyzed esterification with theO-acylisourea or the HOAT active ester of the Fmoc-protected amino acidformed by its reaction with DIC or DIC/HOAT, respectively. Coupling ofthe subsequent amino acids can be accomplished using HOBT or HOAT activeesters produced from DIC/HOBT or DIC/HOAT, respectively.

The syntheses of the 11-mer peptide analogs described herein can becarried out by using a peptide synthesizer, such as an Advanced ChemtechMultiple Peptide Synthesizer (MPS396) or an Applied Biosystems Inc.peptide synthesizer (ABI 433A). If the MPS396 was used, up to 96peptides were simultaneously synthesized. If the ABI 433A synthesizerwas used, individual peptides were synthesized sequentially. In bothcases the stepwise solid phase peptide synthesis was carried oututilizing the Fmoc/t-butyl protection strategy described herein. Thenon-natural non-commercial amino acids present at position 11 and atposition 10 were incorporated into the peptide chain in one of twomethods. In the first approach a Boc- or Fmoc-protected non-naturalamino acid was prepared in solution using appropriate organic syntheticprocedures. The resulting derivative was then used in the step-wisesynthesis of the peptide. Alternatively the required nonnatural aminoacid was built on the resin directly using synthetic organic chemistryprocedures. When a nonnatural non-commercial amino acid was needed forincorporation at position X_(aa6) or at any other X_(aa) position asneeded, the required Fmoc-protected nonnatural amino acid wassynthesized in solution. Such a derivative was then used in stepwisesolid phase peptide synthesis.

Preferred for use in this invention are the Fmoc amino acids derivativesshown below.

Orthogonally Protected Amino Acids used in Solid Phase Synthesis

Protected Amino Acids used in Solid Phase Synthesis

The peptidyl-resin precursors for their respective peptides may becleaved and deprotected using any of the standard procedures describedin the literature (see, for example, D. S. King et al. Int. J. PeptideProtein Res. 36, 1990, 255-266). A preferred method for use in thisinvention is the use of TFA in the presence of water and TIS asscavengers. Typically, the peptidyl-resin is stirred in TFA/water/TIS(94:3:3, v:v:v; 1 mL/100 mg of peptidyl resin) for 1.5-2 hrs at roomtemperature. The spent resin is then filtered off and the TFA solutionis concentrated or dried under reduced pressure. The resulting crudepeptide is either precipitated and washed with Et₂O, or is redissolveddirectly into DMSO or 50% aqueous acetic acid for purification bypreparative HPLC.

Peptides with the desired purity can be obtained by purification usingpreparative HPLC, for example, on a Waters Model 4000 or a ShimadzuModel LC-8A liquid chromatograph. The solution of crude peptide isinjected into a YMC S5 ODS (20×100 mm) column and eluted with a lineargradient of MeCN in water, both buffered with 0.1% TFA, using a flowrate of 14-20 mL/min with effluent monitoring by UV absorbance at 220nm. The structures of the purified peptides can be confirmed byelectro-spray MS analysis.

The following abbreviations are employed in the Examples and elsewhereherein: Ph = phenyl n-BuLi = n-butyllithium Pd/C = Bn = benzyl palladiumon carbon i-Bu = iso-butyl PtO2 = platinum oxide Me = methyl TEA =triethylamine Et = ethyl min = minute(s) Pr = n-propyl h or hr = hour(s)Bu = n-butyl L = liter TMS = trimethylsilyl mL = milliliter TIS =Triisopropylsilane μL = microliter Et₂O = diethyl ether g = gram(s) HOAcor AcOH = acetic acid mg = milligram(s) MeCN = acetonitrile mol =mole(s) DMF = N,N-dimethylformamide mmol = millimole(s) EtOAc = ethylacetate meq = milliequivalent THF = tetrahydrofuran rt = roomtemperature TFA = trifluoroacetic acid sat or sat'd = saturated Et₂NH =diethylamine aq. = aqueous NMM = N-methyl morpholine mp = melting pointNMP = N-methylpyrrolidone Bip = biphenylalanine DCM = dichloromethaneLiBH₄ = lithium borohydride PyBOP reagent =benzotriazol-1-yloxy-tripyrrolidino phosphonium hexafluorophosphate DMAP= 4-(dimethylamino)pyridine EDAC =3-ethyl-3′-(dimethylamino)propyl-carbodiimide hydrochloride (or1-[(3-(dimethyl)amino)propyl])-3-ethylcarbodiimide hydrochloride) FMOC =fluorenylmethoxycarbonyl Boc or BOC = tert-butoxycarbonyl Cbz =carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl HOBT or HOBT•H₂O =1-hydroxybenzotriazole hydrate HOAT = 1-hydroxy-7-azabenzotriazole TLC =thin laer chromatography HPLC = high peformance liquid chromatographyLC/MS = high performace liquid chromatography/mass spectrometry MS orMass Sec = mass spectrometry NMR = nuclear magnetic resonance

Those skilled in the art of peptide chemistry are aware that amino acidresidues occur as both D and L isomers, and that the instant inventioncontemplates the use of either or a mixture of isomers for amino acidresidues incorporated in the synthesis of the peptides described herein.

In one embodiment, the present invention provides a method of making apolypeptide of formula

that mimics the activity of a polypeptide receptor agonist having amessage sequence and an address sequence. In this embodiment, theaddress sequence of the polypeptide confers the ability of a polypeptideto bind to a receptor and the message sequence is capable of inducingreceptor mediated signal transduction upon binding of the polypeptide tothe receptor. The method of making the polypeptide comprises replacingthe message sequence of a polypeptide receptor agonist with Y and Zwherein Y and Z are amino acid residues;

wherein one of the substitutions at the alpha-carbon atoms of Y and Zmay each independently be substituted with a primary substituent groupselected from the group consisting of hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl,heterocyclylalkyl said primary substituent optionally being substitutedwith a secondary substituent selected from a cycloalkyl, heterocyclyl,aryl or heteroaryl group; any of said primary or secondary substituentsmay further be substituted with one or more of, hydrogen, alkyl,cycloalkyl, arylalkyl, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl,halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido,guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl,acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy,heterocycleoxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl,mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl,guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl orphosphonic group; wherein, the primary or secondary substitutents mayoptionally be bridged by covalent bonds to form one or more fused cyclicor heterocyclic systems with each other;

wherein, the other substitution at the alpha-carbon of Y may besubstituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl orcarboxyalkyl;

wherein, the other substitution at the alpha-carbon of Z may besubstituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl orcarboxyalkyl.

In a preferred embodiment, the present invention provides a method ofmaking a polypeptide that mimics the activity of an endogenouspolypeptide receptor agonist. In another preferred embodiment, thepolypeptide receptor agonist is GLP-1. In another aspect, the method ofmaking the polypeptide further comprises replacing the message sequenceof the polypeptide with a variant message sequence capable of inducingreceptor mediated signal transduction. Variant message sequences can bemade by replacing or modifying one or more amino acid residues of apolypeptide receptor agonist message sequence.

EXAMPLE 1 Simultaneous Solid Phase Peptide Synthesis of GLP-1 11-MerPeptide Mimics

Dipeptidyl resin, containing non-natural non-commercial amino acidresidues at positions 10 and 11, was prepared using the following manualprocedure in a batch-wise mode before continuing peptide chainelongation utilizing the automated simultaneous synthesis protocol onthe MPS-396 peptide synthesizer. The synthesis of the Nα-Fmoc-protectedbiphenylalanine derivatives used in the manual couplings is described inExamples 8-10.

An amount of4-(2′,4′-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetyl-p-methylbenzhydrylamine resin (Rink amide MBHA resin; loading: 0.5 mmol/g)sufficient to synthesize several 1′-mer analogs, was swelled by washingwith DMF (4×10 mL/g, 5 minutes). The Fmoc group was then removed usingtwo treatments, 3 and 18 minutes each respectively, with 20% piperidinein DMF (10 mL/g). The resin was washed with DMF (4×10 mL/g) and NMP(4×10 mL/g). A 0.5 M solution of Fmoc-L-biphenylalanine-OH (2.0 eq.), oranalog thereof, and HOAt (2.0 eq.) in NMP was added to the resin,followed by a 1.0 M solution of DIC (2.05 eq.) in NMP. The resin wasthen shaken or vortexed for 16-24 hours. Coupling completion wasmonitored using a qualitative ninhydrin test. The resin was drained,washed with NMP (3×10 mL/g) and DMF (3×10 mL/g), and treated twice, 5and 20 minutes each respectively, with 20% acetic anhydride in DMF (8mL/g). After DMF washes (4×10 mL/g), a second manual coupling cycle wasthen performed as described above, starting from the removal of the Fmocgroup with 20% piperidine in DMF, and using either the same or adifferent Fmoc-protected biphenylalanine analog in the coupling step.This synthesis scheme produced the desired Fmoc-protecteddipeptidyl-Rink amide MBHA resin.

Similar dipeptidyl resins were also obtained by another procedure,described in Examples 5-7, using solid phase Suzuki condensationreactions.

Such dipeptidyl-resins required for the synthesis of a set of designedanalogs were then used in the automated MPS synthesis of up to 96peptides per run in the following manner. The dipeptidyl-resins wereloaded as suspensions in dichloromethane/DMF (60:40) into the 96-wellreactor of an Advanced ChemTech MPS 396 synthesizer in volumescorresponding to 0.01-0.025 mmol (20-50 mg) of resin per reactor well.The reactor was placed on the instrument and drained. The wells werethen washed with DMF (0.5-1.0 mL, 3×2 min) and subjected to the numberof automated coupling cycles required to assemble the respective peptidesequences as determined by the pre-programmed sequence synthesis table.The detailed stepwise synthesis protocol used for a typical 0.01mmol/well simultaneous synthesis of 96 compounds is described below.This protocol was adapted for the simultaneous synthesis of arrays ofanalogs ranging from 12 to 96 per individual run. The general synthesisprotocol is depicted in Scheme I.

Prior to starting the synthesis, the following reagent solutions wereprepared and placed on the instrument as required: 1.5 M (15%)piperidine in DMF; 0.5 M DIEA in NMP; 0.36 M DIC in NMP; 1 M (10%)acetic anhydride in DMF. The required Fmoc-protected amino acids wereprepared as 0.36 M solutions in 0.36 M HOAt/NMP and placed into theappropriate positions in the 32-position amino acid rack.

The Fmoc-protected dipeptidyl-resin prepared above was deprotected bytreating with 1.5 M (15%) piperidine in DMF (0.6 mL; 1×3 minutes; 1×18minutes). The resin was then washed with DMF (4×0.5 mL), DMF/EtOH(80:20) (1×0.5 mL) and NMP (3×0.5 mL).

Coupling of the next amino acid residue, typically Fmoc-Asp(OtBu)-OH oranother Fmoc-amino acid with appropriate orthogonal protection ifrequired, was carried out by automated addition of a 0.36 M solution ofthe appropriate Fmoc-amino acid (0.072 mmol, 7.2 eq.) and HOAt (7.2 eq.)in NMP (0.2 mL) to all 96 wells. This was followed by addition to all 96wells of a 0.36 M solution of DIC (0.072 mmol, 7.2 eq.) in NMP (0.2 mL).The coupling was allowed to proceed for 2 hrs. After reactor draining bynitrogen pressure (3-5 psi) and washing the wells with NMP (1×0.5 mL),the coupling was repeated as described above. At the end of the couplingcycle, the wells were treated with 1M acetic anhydride in DMF (1×0.5 mL,30 min.) and finally washed with DMF (3×0.5 mL).

The next coupling cycle started with the removal of the Fmoc group asdescribed above, and involved the coupling of either Fmoc-Ser(tBu)-OH orof a different Fmoc-amino acid as required by the sequence substitutionsdesired at this position. The coupling was carried out in a manneridentical to that described for Fmoc-Asp(OtBu)-OH. The next couplingstep was carried out in the same way to incorporate eitherFmoc-Thr(tBu)-OH or any of the other selected Fmoc-amino acids into thissequence position as required.

The next Fmoc-amino acid (for example Fmoc-Phe-OH) was coupled asdescribed above. For sequences requiring incorporation of a novelnon-commercially available aromatic or non-aromatic amino acid analog atthis step, the coupling was modified as follows: after Fmoc deprotectionin the usual manner, the Fmoc-amino acid (5 eq.) and HOAt (5 eq.) wereadded manually as a 0.36 M solution in NMP (0.139 mL). The 0.36 Msolution of DIC in NMP (0.139 mL) was then added by the instrument andthe coupling was allowed to proceed for 16-24 hrs. The coupling was notrepeated in this case. After the usual post-coupling washes, thepeptidyl-resins were capped with acetic anhydride as described.

The next coupling step involved either Fmoc-Thr(tBu)-OH or substitutionanalogs as required by sequence replacements at this position. Thecoupling was performed as described for the initial MPS coupling ofFmoc-Asp(OtBu)-OH and its analogs. This identical coupling protocol wasrepeated four additional times in order to complete the sequenceassembly of the desired 96 11-mer peptide analogs. For the coupling ofcommercially and non-commercially available non-natural amino acidsneeded at a certain sequence position, a single coupling protocolsimilar to that described above for the novel amino acid at position 6(X_(aa6)) was used.

Finally, the Fmoc group was removed with 20% piperidine in DMF asdescribed above, and the peptidyl-resins were washed with DMF (4×0.5 mL)and DCM (4×0.5 mL). They were then dried on the reactor block byapplying a constant pressure of nitrogen gas (5 psi) for 10-15 min.

Cleavage/Deprotection

The desired peptides were cleaved/deprotected from their respectivepeptidyl-resins by treatment with a TFA cleavage mixture as follows. Asolution of TFA/water/tri-isopropylsilane (94:3:3) (1.0 mL) was added toeach well in the reactor block, which was then vortexed for 2 hrs. TheTFA solutions from the wells were collected by positive pressure intopre-tared vials located in a matching 96-vial block on the bottom of thereactor. The resins in the wells were rinsed twice with an additional0.5 mL of TFA cocktail and the rinses were combined with the solutionsin the vials. These were dried in a SpeedVac™ (Savant) to yield thecrude peptides, typically in >100% yields (20-40 mgs). The crudepeptides were either washed with ether or more frequently re-dissolveddirectly in 2 mL of DMSO or 50% aqueous acetic acid for purification bypreparative HPLC as follows.

Preparative HPLC Purification of the Crude Peptides

Preparative HPLC was carried out either on a Waters Model 4000 or aShimadzu Model LC-8A liquid chromatograph. Each solution of crudepeptide was injected into a YMC S5 ODS (20×100 mm) column and elutedusing a linear gradient of MeCN in water, both buffered with 0.1% TFA. Atypical gradient used was from 20% to 70% 0.1% TFA/MeCN in 0.1%TFA/water over 15 min. at a flow rate of 14 mL/min with effluent UVdetection at 220 nm. The desired product eluted well separated fromimpurities, typically after 10-11 min., and was usually collected in asingle 10-15 mL fraction on a fraction collector. The desired peptideswere obtained as amorphous white powders by lyophilization of their HPLCfractions.

HPLC Analysis of the Purified Peptides

After purification by preparative HPLC as described above, each peptidewas analyzed by analytical RP-HPLC on a Shimadzu LC-10AD or LC-10ATanalytical HPLC system consisting of: a SCL-10A system controller, aSIL-10A auto-injector, a SPD10AV or SPD-M6A UV/VIS detector, or aSPD-M10A diode array detector. A YMC ODS S3 (4.6×50 mm) column was usedand elution was performed using one of the following gradients: 10-70% Bin A over 8 min, 2.5 mL/min. (method A); 5-80% B in A over 8 min, 2.5mL/min. (method B); 5-70% B in A over 8 min., 2.5 mL/min. (method C);25-75% B in A over 8 min, 2.5 mL/min (method D); 20-75% B in A over 8min, 2.5 mL/min. (method E); 15-70% B in A over 8 min, 2.5 mL/min.(method F); 10-90% B in A over 8 min, 2.5 mL/min. (method G); 20-65% Bin A over 8 min, 2.5 mL/min. (method H); 5-90% B in A over 8 min., 2.0mL/min. (method I); 5-90% B in A over 8 min., 2.5 mL/min. (method J);20-80% B in A over 8 min., 2.5 mL/min. (method K); 10-100% B in A over 8min., 2.5 mL/min. (method L); 10-75% B in A over 8 min., 2.5 mL/min.(method M). Mobile phase A: 0.1% TFA/water; mobile phase B: 0.1%TFA/acetonitrile. The purity was typically >90%.

Characterization by Mass Spectrometry

Each peptide was characterized by electrospray mass spectrometry (ES-MS)either in flow injection or LC/MS mode. Finnigan SSQ7000 singlequadrupole mass spectrometers (ThermoFinnigan, San Jose, Calif.) wereused in all analyses in positive and negative ion electrospray mode.Full scan data was acquired over the mass range of 300 to 2200 amu for ascan time of 1.0 second. The quadrupole was operated at unit resolution.For flow injection analyses, the mass spectrometer was interfaced to aWaters 616 HPLC pump (Waters Corp., Milford, Mass.) and equipped with anHTS PAL autosampler (CTC Analytics, Zwingen, Switzerland). Samples wereinjected into a mobile phase containing 50:50 water:acetonitrile with0.1% ammonium hydroxide. The flow rate for the analyses was 0.42 mL/min.and the injection volume 6 μl. A ThermoSeparations Constametric 3500liquid chromatograph (ThermoSeparation Products, San Jose, Calif.) andHTS PAL autosampler were used for LC/MS analyses. Chromatographicseparations were achieved employing a Luna C₁₈, 5 micron column, 2×30 mm(Phenomenex, Torrance, Calif.). The flow rate for the analyses was 1.0mL/min and column effluent was split, so that the flow into theelectrospray interface was 400 μl/min. A linear gradient from 0% to 100%B in A over 4 minutes was run, where mobile phase A was 98:2water:acetonitrile with 10 mM ammonium acetate and mobile phase B was10:90 water:acetonitrile with 10 mM ammonium acetate. The UV responsewas monitored at 220 nm. The samples were dissolved in 200 μl 50:50H₂O:MeCN (0.05% TFA). The injection volume was 5 μl.

In all cases, the experimentally measured molecular weight was within0.5 Daltons of the calculated mono-isotopic molecular weight.

EXAMPLE 2 Synthesis of N-Acylated and N-Alkylated 11-Mer Peptide Analogs

(A) General Procedure for the Synthesis of N-Alkylated 11-Mer PeptideAnalogs by Reductive Alkylation

The synthesis of N-alkylated 11-mer peptide analogs was started from theprotected intermediate 11-mer peptidyl-resin (1) (0.025 mmol), which wasprepared by the general method described herein. The Fmoc group wasremoved using the procedure described in that method, to yield theprotected resin intermediate 2. This was swollen in DMF, washed 3 timeswith 1% AcOH/DMF, and then treated with 2-20 eq. of aldehyde orN-Boc-protected aminoaldehyde (see synthesis below), dissolved in 1%AcOH/DMF (or CH₂Cl₂) (1 M), and the same excess amount of Na(AcO)₃BH asthat of the aldehyde. After overnight reaction, the resin was drained,washed with DMF and DCM, 3 times each, and dried. The reductivelyalkylated peptide (4) was cleaved and deprotected by treatment withTFA/tri-isopropylsilane/water (90:5:5, v:v:v; 1-2 mL) for 2 hrs. Theresin was filtered off and rinsed with 1 mL of cleavage solution, whichwas combined with the filtrate and dried in a SpeedVac™ (Savant) toyield the crude product. This was purified by preparative HPLC asdescribed in the general peptide synthesis method outlined herein. Thepurity and identity of the desired products were confirmed by analyticalHPLC and electrospray MS.

N-Boc-protected aminoaldehydes were synthesized using Castro's procedure(Fehrentz, J. A., and Castro, B., Synthesis, 1983, 676-678) as follows.The Boc-protected amino acid (2.0 mmol) was dissolved in 5 mL DCM. BOPreagent (1.1 eq.) and DIEA (1.15 eq) were added. After 5 minutes, asolution of N,O-dimethylhydroxylamine (1.2 eq) and DIEA (1.3 eq) in 5 mLDCM was added. The reaction mixture was stirred for 2 hrs, diluted withDCM (30 mL), and washed with 2N HCl (3×), sat. NaHCO₃ (3×) and brine(1×). The organic extracts were dried over MgSO₄, filtered andevaporated to dryness to yield the Weinreb amide. This was thendissolved in ether or THF (10 mL/mmol)) and reacted with a 1 M solutionof LiAlH₄ in THF (2 mL/mmol of hydroxamate) for 30 minutes. The reactionmixture was quenched with 5 mL of 0.35 M KHSO₄, and diluted with ether(20 mL). The aqueous phase was separated and extracted with ether (3×20mL). The combined ether extracts were washed with 2N HCl (2×), sat.NaHCO₃ (2×) and brine (1×), dried over MgSO₄, filtered and evaporated todryness to yield the Boc-protected aldehyde in 20-30% yield. Thealdehyde was characterized by ¹H-NMR and electrospray MS, and was usedin the reductive alkylation step without further purification.

(B) General Procedure for the Synthesis of N-Acylated 11-Mer PeptideAnalogs.

Similarly, the synthesis of the N-acylated 11-mer peptide analogs wasstarted from the protected 11-mer peptidyl-resin intermediate (1) (0.025mmol), prepared as described herein. The Fmoc group was removed usingthe procedure described herein, and the resulting resin intermediate 2was coupled with the relevant Fmoc-protected amino acid or carboxylicacid using the coupling protocol described in the general methoddescribed herein. In cases where the appropriate anhydride wasavailable, the N-acylation was performed using 10 eq. of the anhydridein NMP. The resulting 12-mer analogs (3) were cleaved/deprotected andpurified by prep. HPLC by the general method described herein.

(C) General Procedure for the Synthesis of N-Carbamate Derivatives of1-Mer Peptide Analogs.

The synthesis of N-carbamate derivatives of 11-mer peptide analogs maybe started from the protected 1′-mer peptidyl-resin intermediate (1)(0.025 mmol), prepared as described herein. The Fmoc group is removedusing the procedure described herein, and the resulting resinintermediate 2 is allowed to react with the relevant chloroformate inthe presence of an appropriate base such as a tertiary amine, or with adi-carbonate or an activated carbonate such as p-nitrophenyl or phenylcarbonate. Similarly, N-carbamate derivatives of 10-mer peptide analogsmay be prepared starting from a protected 10-mer peptidyl-resinintermediate, Fmoc removal and reaction of the resulting peptidyl-resinintermediate with the relevant chloroformate, di-carbonate or activatedcarbonate.

(D) General Procedure for the Synthesis of N-Urea Derivatives of 11-MerPeptide Analogs.

The synthesis of N-urea derivatives of 11-mer peptide analogs may bestarted from the protected 1′-mer peptidyl-resin intermediate (1) (0.025mmol), prepared as described herein. The Fmoc group is removed using theprocedure described herein, and the resulting resin intermediate 2 isallowed to react with the relevant isocyanate prepared, for example, asin K. Burgess et al., J. Am. Chem. Soc. 1997, 119, 1556-1564;alternatively, the resin intermediate 2 may be allowed to react with therelevant carbamyl chloride. Similarly, N-urea derivatives of 10-merpeptide analogs may be prepared starting from a protected 10-merpeptidyl-resin intermediate, Fmoc removal and reaction of the resultingpeptidyl-resin intermediate with the relevant isocyanate or carbamylchloride.

(E) General Procedure for the Synthesis of N-Sulfonamides of 11-MerPeptide Analogs.

The synthesis of N-sulfonamides of 11-mer peptide analogs may be startedfrom the protected 11-mer peptidyl-resin intermediate (1) (0.025 mmol),prepared as described herein. The Fmoc group is removed using theprocedure described herein, and the resulting resin intermediate 2 isallowed to react with the relevant sulfonyl chloride. Similarly,N-sulfonamides of 10-mer peptide analogs may be prepared starting from aprotected 10-mer peptidyl-resin intermediate, Fmoc removal and reactionof the resulting peptidyl-resin intermediate with the relevant sulfonylchloride.

(F) General Procedure for the Synthesis of N-Sulfonylurea Derivatives of11-Mer Peptide Analogs.

The synthesis of N-sulfonylurea derivatives of 11-mer peptide analogsmay be started from the protected 11-mer peptidyl-resin intermediate (1)(0.025 mmol), prepared as described herein. The Fmoc group is removedusing the procedure described herein, and the resulting resinintermediate 2 is allowed to react with the relevant sulfamoyl chlorideR₄R₅N—SO₂—Cl to yield a sulfonyl urea intermediate (see, for example, P.Davern et al. J. Chem. Soc., Perkin Trans. 2, 1994 (2), 381-387).Similarly, N-sulfonyl urea derivatives of 10-mer peptide analogs may beprepared starting from a protected 10-mer peptidyl-resin intermediate,Fmoc removal and reaction of the resulting peptidyl-resin intermediatewith the relevant sulfamoyl chloride R₄R₅N—SO₂—Cl.

EXAMPLE 3 Synthesis of N-Arylalkyl Amides of 10-Mer Peptide Analogs

The synthesis of N-arylalkyl amides of 10-mer peptide analogs wasstarted with a reductive alkylation reaction of a relevantarylalkylamine with an alkoxybenzaldehyde resin as in the followingexample. 2-(3,5-Dimethoxy-4-formylphenoxy)ethoxymethyl polystyrene resin(Novabiochem, 1.12 mmol/gram, 0.025 mmol, 27.3 mg) was washed with 1%Acetic Acid in DCM (5×3 mL). A solution of 2-(2-pentafluorophenyl)ethylamine (0.125 mmol, 26.4 mg) in DCM (3 mL) was added to the resin. After5 minutes, solid NaBH(OAc)₃ (0.125 mmol, 26.5 mg,) was added and thereaction was vortexed for 16 hours. The resin was rinsed with DMF (5×3mL) and DCM (5×3 mL).

A solution of Fmoc-[BIP(2-Et)]-OH (0.05 mmol, 25.3 mg) and HOAt (0.05mmol, 6.81 mg) in NMP(0.5 mL) was added to the resin followed by DIC(0.05 mmol, 7.82 μL). The reaction was vortexed for 16 hrs. The resinwas rinsed with NMP(5×3 mL). The remaining sequence of the desired10-mer N-arylalkyl amide analog was then assembled as described inExample 1.

EXAMPLE 4 Solid Phase Synthesis of 11-mer Peptide Analogs Using anApplied Biosystems Model 433A Peptide Synthesizer

Following is the general description for the solid phase synthesis oftypical 11-mer peptide analogs, using an upgraded Applied BiosystemsModel 433A peptide synthesizer. The upgraded hardware and software ofthe synthesizer enabled conductivity monitoring of the Fmoc deprotectionstep with feedback control of coupling. The protocols allowed a range ofsynthesis scale from 0.05 to 1.0 mmol.

The incorporation of the two non-natural C-terminal amino acid residueswas described earlier in connection with simultaneous synthesis of11-mer analogs. Such a Fmoc-protected dipeptidyl resin was used in thisABI synthesis. The Fmoc-protected dipeptidyl-resin (0.1 mmol) was placedinto a vessel of appropriate size on the instrument, washed 6 times withNMP and deprotected using two treatments with 22% piperidine/NMP (2 and8 min. each). One or two additional monitored deprotection steps wereperformed until the conditions of the monitoring option were satisfied(<10% difference between the last two conductivity-based deprotectionpeaks). The total deprotection time was 10-12 min. The deprotecteddipeptidyl-resin was washed 6 times with NMP and then coupled with thenext amino acid. The procedure is illustrated by the example used in thenext step. Thus, Fmoc-Asp(OtBu)-OH was coupled next using the followingmethod: Fmoc-Asp(OtBu)-OH (1 mmol, 10 eq.) was dissolved in 2 mL of NMPand activated by subsequent addition of 0.45 M HBTU/HOBt in DMF (2.2 mL)and 2 M DIEA/NMP (1 mL). The solution of the activated Fmoc-protectedamino acid was then transferred to the reaction vessel and the couplingwas allowed to proceed for 30 to 60 min., depending on the feedback fromthe deprotection steps. The resin was then washed 6 times with NMP, andsubjected to 8 additional deprotection/coupling cycles as describedabove in order to complete the assembly of the desired sequence. TheFmoc-amino acids sequentially used were: Fmoc-Ser(tBu)-OH,Fmoc-Thr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Thr(tBu)-OH, Fmoc-Gly-OH,Fmoc-Glu(OtBu)-OH, Fmoc-Ala-OH and Fmoc-His(Trt)-OH. Finally, the Fmocgroup was removed with 22% piperidine in NMP as described above, and thepeptidyl-resin was washed 6 times with NMP and DCM, and dried in vacuo.

Alternatively, a modified coupling protocol was used in which theFmoc-protected amino acid (1 mmol) was activated by subsequent additionof 0.5 M HOAt in NMP (2 mL) and 1 M DIC/NMP (1 mL), transferred to thereaction vessel and allowed to couple for 1-2 hrs.

Cleavage/Deprotection

The desired peptide was cleaved/deprotected from its respectivepeptidyl-resin (0.141 g) by treatment with a solution ofTFA/water/tri-isopropylsilane (94:3:3) (2.5 mL) for 2 hrs. The resin wasfiltered off, rinsed with TFA cleavage solution (0.5 mL), and thecombined TFA filtrates were dried in vacuo. The resulting solid wastriturated and washed with diethyl ether, and finally dried, to yield35.6 mg (58%) of crude peptide product as a white solid. This waspurified by preparative HPLC as described herein. The gradient used wasfrom 20% to 75% 0.1% TFA/MeCN in 0.1% TFA/water over 15 min. Thefraction containing a pure product was lyophilized, to yield 7.2 mg (20%recovery) of pure product.

EXAMPLE 5 Synthesis of Biphenylalanine Analogs at Position-10 andPosition-11

For those analogs wherein position-10 and position-11 residues wererepresented by substituted phenylalanine analogs, i.e. biphenylalanineanalogs (Bip-analogs), their incorporation into the peptide chain wascarried out in one of two approaches.

Approach A: Solid Phase Suzuki Condensation

In approach A, solid phase Suzuki condensation was practiced to preparethe required modified phenylalanine residue in a manner suitable forcarrying out subsequent solid phase peptide synthesis to obtain thetarget peptides. When the amino acid at position-11 in the targetpeptide was represented by a modified phenylalanine residue, it wasprepared as shown in Scheme 3. After removal of the Boc α-amineprotecting group, chain elongation was continued using multiple peptidesynthesis as described in the previous section to obtain the desired11-mer peptides or its derivatives thereof. When the modifiedphenylalanine analog was in position-10 of the target peptides, therequired amino acid was prepared using a suitable dipeptide resin asshown in Scheme 4. The resulting dipeptidyl resin containing therequired modified phenylalanine derivative was then used to carry outthe synthesis of the target 11-mer peptide or its derivatives thereof.When both position-10 and position-11 required novel biphenylalanineresidues, two sequential solid phase Suzuki reactions were carried outas shown in Scheme 5.General Procedure for Preparation of Resin Containing BiphenylalanineResidue at Position-11 (Suzuki Couplings).

Procedure A:

Polystyrene (1% DVB crosslinked) resins (50 mg, 0.025 mmole) derivatizedwith an Nα-Boc-4-iodophenylalanine residue either attached directly viaa Knorr linkage (Boc-amino acid-resin) or via an amino acid-Knorrlinkage (Boc-dipeptide-resin) were weighed into 13×100 mm glass culturetubes with screw caps. Aryl-boronic acids (0.5 mmole) were dissolved in0.75 ml of 25% by volume diisopropylethylamine in N-methylpyrrolidinoneand added to the resins followed by 0.05 ml of an N-methylpyrrolidinonesolution containing 1.0 mg of tetrakis(triphenylphospine)palladium(0)catalyst (ca. 3.5 mole %). The resulting mixtures were blanketed with astream of nitrogen and the reaction vessels tightly capped andmaintained at 85-90° C. for 17-20 hours with periodic shaking. Theresins were washed with 5×1 ml of N-methylpyrrolidinone and 5×1 ml ofdichloromethane prior to Boc group cleavage (see General Procedurebelow).

Procedure B:

The reactions were performed as in General Procedure A except adifferent catalyst was employed. The catalyst solution was prepared bydissolving 9.0 mg of palladium(II) acetate and 56 mg of2-(dicyclohexylphosphino)biphenyl in 2.0 ml of N-methylpyrrolidinone.For 0.025 mmole scale reactions, 0.038 ml (ca. 3 mole %) of catalystsolution was employed.

Procedures for Cleavage of the Boc Group

Method A: The Boc-protected resins prepared as described in GeneralProcedures A or B were treated with 0.5 ml of reagent solutionconsisting of trimethylsilyl trifluoromethanesulfonate, 2,6-lutidine anddichloromethane (1:1:3 by volume). After 3 such reagent treatments for 1hour each with shaking, the resins were washed with 4×1 ml ofdichloromethane, 3×1 ml of N,N-dimethylformamide, 3×1 ml of 20% MeOH inN,N-dimethylformamide and 4×1 ml dichloromethane prior to transfer tothe automated peptide synthesizer.

Method B: The Boc-protected resins prepared as described in GeneralProcedures A or B were treated with 1.0 ml of 1N HCl in anhydrous1,4-dioxane for 1 hour at room temperature with shaking. The resins werewashed with 4×1 ml of dichloromethane, 3×1 ml of 5%diisopropylethylamine in dichloromethane (vol:vol), 3×1 ml ofdichloromethane, and 5×1 ml of N-methylpyrrolidinone to provide the freeamino-resins ready for the next acylation (coupling reaction) step.

EXAMPLE 6 General Procedure for Preparation of a Resin Containing aModified Biphenylalanine Residue at Position-10

The general procedures described above (A or B) for Suzuki coupling wereutilized to obtain the required dipeptidyl resin containing modified Pheat position-10 starting with the amino acid (at position-11) bound resinas shown in Scheme 4.

EXAMPLE 7 General Procedure for Preparation of Resin ContainingBiphenylalanine Residues at Both Positions 10 and 11

Utilizing the procedures described for position 11 modified analogs(Scheme 1) and carrying out the Suzuki coupling procedure two successivetimes produced dipeptidyl resins containing modified phenylalanineresidues at both positions-10 and -11 as illustrated in Scheme 5.

Approach B: Synthesis of Fmoc-Biphenylalanine Derivatives Using SuzukiCondensation in Solution.

Using this method, exemplified by the synthesis ofFmoc-2-methyl-biphenylalanine, several N-α-Fmoc protectedbiphenylalanine derivatives were prepared. They were utilized for thesolid phase synthesis of 11-mers and other peptide analogs as describedherein.

EXAMPLE 8 Synthesis of Fmoc-2-methyl-biphenylalanine

The following scheme 6 describes the synthesis ofFmoc-2-methyl-biphenylalanine.

Boc-L-Tyrosine-O-triflate: To a solution of 37 g (126 mmol ofBoc-tyrosine methyl ester, and 25.4 mL (314 mmol, 2.5 eq.) of pyridinein 114 mL of dry dichloromethane, kept at −15° C. under N₂, was addedslowly 25.4 mL (151 mmol, 1.2 eq.) of triflic anhydride. The solutionwas stirred at −15° C. for 15 min. HPLC analysis indicated that thereaction was complete. The reaction was quenched by addition of 150 mLof water. The layers were separated, and the organic layer washed with2×150 mL of 0.5M NaOH, and 2×150 mL of 15% citric acid solution. Theorganic layer was dried over magnesium sulfate, filtered concentratedand dried in vacuo to give the crude product as a red oil. (Crude yieldvaried between 90% to quantitative).

Boc-(2-Me) biphenylalanine methyl ester: The above red oil was dissolvedin 70 mL of toluene, and added to a degassed suspension containing 19.0g (140 mmol, 1.2 eq.) of o-tolyllboronic acid, 24.1 g (175 mmol, 1.5eq.) of potassium carbonate, and 4.6 g (4.0 mol, 0.034 eq.) oftetrakis(triphenylphosphine) palladium (0) in 580 mL of toluenepreheated at 80° C. The mixture was heated at 80° C. under N₂ for 3 h,cooled to room temperature, and then filtered through celite. Thereaction mixture was washed with 2×150 mL of 0.5% of NaOH, and 2×150 mLof 15% citric acid solution, dried over magnesium sulfate andconcentrated. The crude mixture thus obtained was purified by silica gelchromatography using ethyl acetate/heptane (1:9) as eluant, [crudemixture was preabsorbed on silica gel (2 g silica gel/g crude mixture),1:35:: mixture:silica gel used for the column], yield varied from 50 to80%.

Boc-(2-Me) biphenylalanine: To a solution of 44.5 g (120 mmol) ofBoc-(2-Me) biphenylalanine methyl ester in 147 mL of methanol and 442 mLof tetrahydrofuran, kept at room temperature, was added 147.4 mL of 1NNaOH (147 mmol, 1.2 eq.). HPLC analysis indicated that the reaction wascomplete after 1 h. The reaction mixture was concentrated andpartitioned between 500 mL of water and 300 mL of ether. The etherealsolution was discarded. Aqueous layer was acidified with 160 mL of 1 NHCl solution, and then extracted with 2×250 mL of ethyl ether. Theethereal solutions were combined, and dried over magnesium sulfate.After filtration, concentration and drying 41.5 g of product wasobtained.

Fmoc-(2-Me) biphenylalanine: To a solution of 41.5 g (117 mmol) ofBoc-(2-Me) biphenylalanine in 1 L of dichloromethane, kept at roomtemperature, was bubbled in gaseous HCl. A white solid started toprecipitate in approximately 5 min. HPLC taken after 2 hours showed thatthe reaction was complete. The mixture was concentrated. The residue wasredissolved in 600 mL of tetrahydrofuran and 150 mL of water, and solidNaHCO₃ was added slowly until the pH of the mixture was basic (a whitesolid precipitated out), followed by addition of 38.9 g (115 mmol, 1eq.) of Fmoc-Osu. The mixture was then stirred at room temperature. Ahomogeneous biphasic solution was obtained within 1 h. The stirring wascontinued at room temperature under N₂ overnight. The layers wereseparated. The tetrahydrofuran layer was acidified with 58 mL 2N HCl,and then diluted with 400 mL of ethyl acetate. The layers wereseparated, and the organic layer washed with 2×100 mL of water, driedover magnesium sulfate, and concentrated. The crude product was purifiedusing silica gel column chromatography using dichloromethane as eluantuntil most of the impurities had been removed. The solvent was thenchanged to 25% ethyl acetate in heptane containing 1% acetic acid,[approximately 23 g silica gel/g crude mixture used for the column]. Theyield was >90% for the three steps.

EXAMPLE 9 General Synthesis of Various Fmoc-biphenylalanine Derivatives

Synthesis of various biphenyl alanine derivatives were carried out usingthe above described procedure, starting with the commercially availablephenol derivative (e.g. Boc-Tyrosine methyl ester) to prepare thetriflate and using the appropriate boronic acid to prepare thebiphenylalanine analogs. When a required boronic acid was not availablefrom commercial sources the synthesis of this intermediate was carriedout as exemplified in the following example.

2-Ethylphenyl boronic acid: To a solution of 25 g (135 mmol) of1-bromo-2-ethylbenzene in 280 mL of dry tetrahydrofuran, kept at −78° C.in an oven-dried 3 neck flask, was added slowly (keeping the temperaturebelow −68° C.) 67.5 mL of 2.5N n-Butyl lithium in hexanes solution (169mmol, 1.25 eq.). The reaction was stirred for an additional 1 h, andthen 69 mL (405 mmol, 3 eq.) of triethylborate was added slowly, keepingthe temperature below −68° C. The reaction was stirred for an additional40 minutes and then the dry ice bath was removed, the reaction wasallowed to warm up to room temperature, and then was poured into 300 mLof ice cold saturated ammonium chloride solution. 200 mL of ice coldethyl acetate was added, and the mixture stirred for another 30 min. Thelayers were separated. The organic layer was washed with water, andbrine. It was then dried over magnesium sulfate, and concentrated togive 19 g (92% yield) of product. The boronic acid was used withoutpurification in the next step.

EXAMPLE 10 Synthesis of Fmoc-Protected Biphenylalanine Analogs withSubstitution in the Internal Phenyl Ring

Synthesis of the Fmoc-protected biphenylalanine analogs withsubstitution in the phenyl ring directly attached to the β-carbon(internal ring) of the amino acid moiety was carried as depicted in thefollowing scheme 7.

As a general method, initially a suitably protected tyrosine derivativewas prepared by reaction of Boc-□-iodo alanine with the required4-iodophenol derivative using a zinc mediated condensation. The productfrom this reaction was subjected to Suzuki condensation reaction asdescribed herein, to afford the required Fmoc-protected biphenylalanineanalogs with substitution in the phenyl ring directly attached to theβ-carbon (internal ring) of the amino acid moiety. Synthesis of aspecific example, Fmoc-2′-methyl-2-methyl-biphenylalnine is given below.

Boc-2′-Methyl-Tyrosine benzyl ether methyl ester: 2.2 g (33 mmol) ofoven-dried zinc dust was placed in an oven dried flask under nitrogen.5.2 mL of dry tetrahydrofuran, and 140 μL (1.6 mmol) of1,2-dibromoethane were added, and the mixture warmed briefly with a heatgun until the solvent began to boil, and then stirred vigorously for afew minutes. This procedure was repeated five times, and then thereaction mixture was cooled to 35° C. 40 μL (0.32 mmol) ofchlorotrimethylsilane was added, and the mixture stirred vigorously at35° C. for 30 min. A solution of 3 mL of 1.04 g (3.17 mmol) ofBoc-iodoalanine methyl ester in 1:1 tetrahydrofuran:dimethylacetamidewas added slowly, and the reaction mixture stirred at 35° C. for 30 min.A solution of 3 mL of 1:1 tetrahydrofuran:dimethylacetamide containing819 mg (2.5 mmol) of 4-iodo-2-methyl-1-benzyloxybenzene was addedslowly, followed by 338 mg (1.11 mmol) of tri-o-tolylphosphine, and 288mg (0.31 mmol) of Pd₂(dba)₃. The reaction mixture was degassed, and thenstirred at 60° C. for 4 h. The reaction mixture was cooled to roomtemperature, diluted with ethyl acetate, and filtered through celite.The filtrate was washed with 2×25 mL of 1N HCl, dried over magnesiumsulfate, filtered and concentrated. The product was purified by silicagel chromatography (72% yield).

Boc-2′-Methyl-Tyrosine methyl ester: A suspension of 7.5 g (18.7 mmol)of the above compound (Boc-2′-methyl-tyrosine benzyl ether methyl ester)in 30 mL of tetrahydrofuran, and 2.25 g 10% Degussa type 10% palladiumon carbon was stirred under hydrogen atmosphere at room temperature andatmospheric pressure for 2 days. The reaction mixture was then filteredthrough celite, and concentrated. The product was purified by silica gelchromatography (74% yield).

Fmoc-2′-methyl-2-methyl-biphenyl alanine: This compound was preparedusing the Suzuki Condensation procedure described herein, usingBoc-2′-Methyl-Tyrosine methyl ester as the starting material. Theproduct obtained in the above Suzuki condensation reaction, afterremoval of the Boc-group and reprotection with Fmoc-group usingconditions described herein afforded the desired product.

EXAMPLE 11

Utilizing the synthetic methods described herein the following GLP-1mimic peptides were prepared

The peptide sequences listed below contain a free amino group at theN-terminus and a carboxamide at the C-terminus. The amino acids shown inTables I-IV are contiguous. TABLE I SEQ ID NO: Xaa1 Xaa2 Xaa3 Xaa4 Xaa5Xaa6 Xaa7 Xaa8 Xaa9 Y Z 1. H A E G T F T S D Bip Phe(4-NO2) 2. H A E G TF T S D Bip 2-Nal 3. H A E G T F T S D Bip Bip 4. H A E G T F T S D BipPhe(penta-Fluoro) 5. H A E G T F T S D Bip Phe(4-Me) 6. H A E G T F T SD 2-Nal Bip 7. H A E G T F T S D Bip F 8. H A E G T F T S D Bip Y 9. H AE G T F T S D 2-Nal Phe(penta-Fluoro) 10. H A E G T F T S D BipPhe(4-Iodo) 11. H A E G T F T S D Bip(2-Me) Bip(4-OMe) 12. H A E G T F TS D Bip(2-Me) Bip(3,4- Methylenedioxy) 13. H A E G T F T S D Bip(2-Me)4-(1-Naphthyl)-Phe 14. H A E G T F T S D Bip(2-Me) Bip(4-Me) 15. H A E GT F T S D Bip(2-Me) Bip(3-Me) 16. H A E G T F T S D Bip(2,4-di-OMe)Bip(2-Me) 17. H A E G T F T S D Bip(2-Me, 4-OMe) Bip(2-Me) 18. H A D G TF T S D Bip(2-Me) Bip(2-Me) 19. H A E G Nle F T S D Bip(2-Me) Bip(2-Me)20. H A E G T Phe(penta- T S D Bip(2-Me) Bip(2-Me) Fluoro) 21. H A H G TPhe(penta- T S D Bip(2-Me) Bip(2-Me) Fluoro) 22. H A D G Nle F T S DBip(2-Me) Bip(2-Me) 23. H A E G Nle Phe(penta- T S D Bip(2-Me) Bip(2-Me)Fluoro) 24. H A E G Nle F T H D Bip(2-Me) Bip(2-Me) 25. H ala D G Nle FT S D Bip(2-Me) Bip(2-Me) 26. H ala D G T Phe(penta- T S D Bip(2-Me)Bip(2-Me) Fluoro) 27. H A H G Nle Phe(penta- T S D Bip(2-Me) Bip(2-Me)Fluoro) 28. H A H G T Phe(penta- T H D Bip(2-Me) Bip(2-Me) Fluoro) 29. HA D G T Phe(penta- T H D Bip(2-Me) Bip(2-Me) Fluoro) 30. H A D G Nle F TH D Bip(2-Me) Bip(2-Me) 31. H ala D G Nle Phe(penta- T S D Bip(2-Me)Bip(2-Me) Fluoro) 32. H A E G T F T S D Bip(2-Et) Bip 33. H A E G NlePhe(penta- T H D Bip(2-Me) Bip(2-Me) Fluoro) 34. H A E G T F T S DBip(2-OEt) Bip(2-Me) 35. H A E G T F T S D Bip(2-Propyl) Bip(2-Me) 36. HA E G T F T S D Bip(2-Propyl,4-OMe) Bip(2-Me) 37. H A E G T F T S DBip(2- Bip Trifluoromethyl) 38. H A E G T F T S D Bip(2-Chloro Bip 39. HA E G T F T S D Bip(4-Fluoro) Bip 40. H A E G T F T S D Bip(4- BipTrifluoromethyl) 41. H A E G T F T S D 4-(1-Naphthyl)-Phe Bip 42. H A EG T F T S D 4-(3-thiophene)-Phe Bip 43. H A E G T F T S D4-(3-Quinoline)-Phe Bip 44. H A E G T F T S D Bip(2-Me)Phe(penta-Fluoro) 45. H A E G T F T S D Bip(2-OMe) Phe(penta-Fluoro) 46.H A E G T F T S D Bip(2- Phe(penta-Fluoro) Trifluoromethyl) 47. H A E GT F T S D Bip(2- Phe(penta-Fluoro) Trifluoromethyl) 48. H A E G T F T SD Bip(2-Chloro) Phe(penta-Fluoro) 49. H A E G T F T S D Bip(2-Fluoro)Phe(penta-Fluoro) 50. H A E G T F T S D Bip(4-OMe) Phe(penta-Fluoro) 51.H A E G T F T S D Bip(3,4- Phe(penta-Fluoro) Methylenedioxy) 52. H A E GT F T S D Bip(2-Me) 2-Nal 53. H A E G T F T S D Bip(2-OMe) 2-Nal 54. H AE G T F T S D Bip(2- 2-Nal Trifluoromethyl) 55. H A E G T F T S DBip(2-Chloro) 2-Nal 56. H A E G T F T S D Bip(2-Fluoro) 2-Nal 57. H A EG T F T S D Bip(4-Me) 2-Nal 58. H A E G T F T S D Bip(4-OMe) 2-Nal 59. HA E G T F T S D Bip(3,4- 2-Nal Methylenedioxy) 60. H A E G T F T S D4-(1-Naphthyl)-Phe 2-Nal 61. H A E G T F T S D 4-(3-thiophene)-Phe 2-Nal62. H A E G T F T S D Bip(2-Me) Phe(4-Me) 63. H A E G T F T S D Bip(2-Phe(4-Me) Trifluoromethyl) 64. H A E G T F T S D Bip(2-Chloro) Phe(4-Me)65. H A E G T F T S D Bip(2-Fluoro) Phe(4-Me) 66. H A E G T F T S DBip(4-Chloro) Phe(4-Me) 67. H A E G T F T S D Bip(4-Me) Phe(4-Me) 68. HA E G T F T S D Bip(4-Fluoro) Phe(4-Me) 69. H A E G T F T S D Bip(4-OMe)Phe(4-Me) 70. H A E G T F T S D Bip(3,4- Phe(4-Me) Methylenedioxy) 71. HA E G T F T S D 4-(1-Naphthyl)-Phe Phe(4-Me) 72. H A E G T F T S DBip(3-Phenyl) Phe(4-Me) 73. H A E G T F T S D Bip(2-Me) Bip(2-Fluoro)74. H A E G T F T S D Bip(2-Me) Bip(4-Phenyl) 75. H A E G T F T S DBip(2-Me) Bip(3-OMe) 76. H A E G T F T S D Bip(2-Me) 4-(3-Pyridyl)-Phe77. H A E G T F T S D Phe(penta-Fluoro) Bip(4-OMe) 78. H A E G T F T S DBip(2-Me) Bip(3-Acetamido) 79. H A E G T F T S D Bip(2-Me)Bip(4-Isopropyl) 80. H A E G T F T S D Bip 4-(1-Naphthyl)-Phe 81. H A EG T F T S D Bip 4-(3-Pyridyl)-Phe 82. H A E G T F T S DPhe(penta-Fluoro) Bip(2-Me) 83. H A E G T F T S D 2-Nal Bip(2-Me) 84. HA E G T F T S D Phe(4-Iodo) Bip(2-Me) 85. H A E G T F T S DPhe(3,4-di-Chloro) Bip(2-Me) 86. H A E G T F T S D Tyr(Bzl) Bip(2-Me)87. H A E G T F T S D homoPhe Bip(2-Me) 88. H A E G T F T S DBip(2,4-di-OMe) Bip 89. H A E G T F T S D 4-(4-(3,5- Bipdimethylisoxazole))- Phe 90. H A E G T F T S D Bip(2-Me, 4-OMe) Bip 91.H A E G T F T S D Bip(2,6-di-Me) Bip 92. H A E G T F T S DBip(2,4-di-Me) Bip 93. H A E G T F T S D Bip(2,3-di-Me) Bip 94. H A E GT F T S D Bip(4- Bip Trifluoromethoxy) 95. H A E G T F T S D Bip(4-Et)Bip 96. H A E G T F T S D 4-(2-Naphthyl)-Phe Bip 97. H A E G T F T S D4-(4- Bip Dibenzofuran)-Phe 98. H A E G T F T S D Bip(2,6-di-OMe)Bip(2-Me) 99. H A E G T F T S D 4-(2,4- Bip(2-Me) dimethoxypyrimidine)-Phe 100. H A E G T F T S D Bip(2,4,6-Trimethyl) Bip(2-Me) 101. H A E G TF T S D 4-(4-(3,5- Bip(2-Me) dimethylisoxazole))- Phe 102. H A E G T F TS D Bip(2,4-di-Chloro) Bip(2-Me) 103. H A E G T F T S D Bip(2,6-di-Me)Bip(2-Me) 104. H A E G T F T S D Bip(2,4-di-Me) Bip(2-Me) 105. H A E G TF T S D Bip(2,3-di-Me) Bip(2-Me) 106. H A E G T F T S D Bip(4-Et)Bip(2-Me) 107. H A E G T F T S D Bip(4-SMe) Bip(2-Me) 108. H A E G T F TS D Bip(4-OEt) Bip(2-Me) 109. H A E G T F T S D 4-(2-Naphthyl)-PheBip(2-Me) 110. H A E G T F T S D 4-(2- Bip(2-Me) Benzo(b)thiophene)-Phe111. H A E G T F T S D 4-(2-Benzo(b)furan)-Phe Bip(2-Me) 112. H A E G TF T S D 4-(4-Dibenzofuran)-Phe Bip(2-Me) 113. H A E G T F T S D4-(4-Phenoxathiin)-Phe Bip(2-Me) 114. H A E G T F T S D Bip(2-Me)Bip(4-Et) 115. H A E G T F T S D Bip(2-Me) Bip(4-SMe) 116. H A E G T F TS D Bip(2-Me) Bip(2,4-di-Me) 117. H A E G T F T S D Bip(2-Me) Bip(2-Me,4-OMe) 118. H A E G T F T S D Bip(2-Me) Bip(2,3-di-Me) 119. H A E G T FT S D Bip(2-Me) 4-(2-naphthyl)-Phe 120. H A E G T F T S D Bip(2-Me)Bip(2-OEt) 121. H A E G T F T S D Bip(2-Me) Bip(2-Et, 4-OMe) 122. H A EG T F T S D Bip(2-Et) Bip(3-Et) 123. H A E G T F T S D Bip(2-Et)Bip(3-Propyl) 124. H A E G T F T S D Bip(2-Et) Bip(3-Phenyl) 125. H A EG T F T S D Bip(2-Et) Bip(3-OEt) 126. H A E G T F T S D Bip(2-Et)Bip(4-Et) 127. H A E G T F T S D Bip(2-Et) Bip(4-SMe) 128. H A E G T F TS D Bip(2-Et) Bip(4-OCF3) 129. H A E G T F T S D Bip(2-Et) Bip(4-OEt)130. H A E G T F T S D Bip(2-Et) Bip(2-Me, 4-OMe) 131. H A E G T F T S DBip(2-Et) Bip(2,6-di-Me) 132. H A E G T F T S D Bip(2-Et)Bip(2,4,6-tri-Me) 133. H A E G T F T S D Bip(2-Et) Bip(2-Phenyl) 134. HA E G T F T S D Bip(2-Et) Bip(2-Isopropyl) 135. H A E G T F T S DBip(2-Et) 4-(2-naphthyl)-Phe 136. H A E G T F T S D Bip(2-Et)Bip(2,5-di-OMe) 137. H A E G T F T S D Bip(2-Et) Bip(2-OEt) 138. H A E GT F T S D Bip(2-Et) Bip(3,4-di-OMe) 139. H A E G T F T S D Bip(2-Et)Bip(2-Et, 4-OMe) 140. H ala E G Nle Phe(penta- T S D Bip(2-Me) Bip(2-Me)Fluoro) 141. H A H G T F T H D Bip(2-Me) Bip(2-Me) 142. H A H G T F T SD Bip(2-Me) Bip(2-Me) 143. H A E G T F T S D Bip Phe(4- Trifluoromethyl)144. H Aib E G Nle Phe(penta- T S D Bip(2-Et) Bip(2-Me) Fluoro) 145. HAib D G T F T S D Bip(2-Et) Bip(2-Me) 146. H Aib D G Nle F T H DBip(2-Et) Bip(2-Me) 147. H Aib H G T Phe(penta- T H D Bip(2-Et)Bip(2-Me) Fluoro) 148. H Aib D G Nle F T S D Bip(2-Et) Bip(2-Me) 149. HAib H G T F T H D Bip(2-Et) Bip(2-Me) 150. H ala asp G Nle Phe(penta- TS D Bip(2-Me) Bip(2-Me) Fluoro) 151. H A D G Nle F T H D Bip(2-Et)Bip(2-Me) 152. H ala D G Nle Phe(penta- T H D Bip(2-Et) Bip(2-Me)Fluoro) 153. H A D G T (L)-Phe(2,4- T S D Bip(2-Me) Bip(2-Me) di-Fluoro)154. H Aib asp G Nle Phe(penta- T S D Bip(2-Me) Bip(2-Me) Fluoro) 155. HA D G T (D)-Phe(2,4- T S D Bip(2-Me) Bip(2-Me) di-Fluoro) 156. H Aib D GNle F T H D Bip(2-Me) Bip(2-Me) 157. H Aib D G Nle F T S D Bip(2-Me)Bip(2-Me) 158. H Aib D G T F T S D Bip(2-Me) Bip(2-Me) 159. H Aib D G TPhe(penta- T S D Bip(2-Me) Bip(2-Me) Fluoro) 160. H Aib E G Nle F T S DBip(2-Me) Bip(2-Me) 161. H Aib E G Nle Phe(penta- T H D Bip(2-Me)Bip(2-Me) Fluoro) 162. H Aib E G Nle Phe(penta- T S D Bip(2-Me)Bip(2-Me) Fluoro) 163. H Aib E G T Phe(penta- T H D Bip(2-Me) Bip(2-Me)Fluoro) 164. H Aib E G T Phe(penta- T S D Bip(2-Me) Bip(2-Me) Fluoro)165. H Aib H G T F T H D Bip(2-Me) Bip(2-Me) 166. H Aib H G T F T S DBip(2-Me) Bip(2-Me) 167. H Aib H G T Phe(penta- T H D Bip(2-Me)Bip(2-Me) Fluoro) 168. his Aib D G Nle Phe(penta- T S D Bip(2-Me)Bip(2-Me) Fluoro) 169. H ala D G Nle Phe(penta- T S D Bip(2-Et)Bip(2-Me) Fluoro) 170. H Aib D G Nle Phe(penta- T S D Bip(2-Et)Bip(2-Me) Fluoro) 171. Aib D G Nle Phe(penta- T S D Bip(2-Me) Bip(2-Et)Fluoro) 172. H Aib D G Nle Phe(penta- T S D Phe(penta-Fluoro) Bip(2-Me)Fluoro) 173. H ala D G T Phe(penta- T S D Bip(2-Et) Bip(2-Me) Fluoro)174. H Aib E G T Phe(penta- T S D Bip(2-Et) Bip(2-Me) Fluoro) 175. H A DG T (L)-Phe(2,5- T S D Bip(2-Me) Bip(2-Me) di-F) 176. H A Dpr G TPhe(penta- T S D Bip(2-Et) Bip(2-Me) Fluoro) 177. H Aib Dpr G TPhe(penta- T S D Bip(2-Et) Bip(2-Me) Fluoro) 178. H ala Dpr G NlePhe(penta- T S D Bip(2-Et, 2′-Me) Bip(2-Me) Fluoro) 179. H A Dpr G TPhe(penta- T S D Bip(2-Et, 2′-Me) Bip(2-Me) Fluoro) 180. H A Dpr G T F TS D Bip(2-Et, 2′-Me) Bip(2-Me) 181. H Iva E G T F T S D Bip(2-Me)Bip(2-Me) 182. H A E G homo F T S D Bip(2-Me) Bip(2-Me) Leu Me) 183. H AE G T homoLeu T S D Bip(2-Me) Bip(2-Me) 184. H A E G T F T S D 2-(9,10-Bip(2-Me) Dihydrophenanthrenyl)- Ala 185. H A E G T F T S D Bip(2-Et)2-(9,10- Dihydrophenanthrenyl)- Ala 186. H A E G T F T S D Bip(2-Et)2-(9,10- Dihydrophenanthrenyl)- Ala 187. H A E G T F T S D 2-(9,10-2-(9,10- Dihydrophenanthrenyl)- Dihydrophenanthrenyl)- Ala Ala 188. H AE G T F T S D 2-(9,10- 2-(9,10- Dihydrophenanthrenyl)-Dihydrophenanthrenyl)- Ala Ala 189. H A E G T F T S D 2-FluorenylAla2-(9,10- Dihydrophenanthrenyl)- Ala 190. H A E G T F T S D 2-(9,10-2-Fluorenyl Dihydrophenanthrenyl)- Ala Ala 191. H A E G T F T S D2-(9,10- 2-Fluorenyl Dihydrophenanthrenyl)- Ala Ala 192. H A E G T F T SD Bip(2-Et, 2′-Et) Bip 193. H A E G T F T S D Bip(2-Et, 2′-Et) Bip(2-Me)194. H ala D G Nle Phe(penta- T S D Bip(2-Et, 4-OMe) Bip(2-Me) Fluoro)195. H A E G T F T S D Bip(2-Propyl, 2′-Me) Bip 196. H A D G TL-α-Me-Phe T S D Bip Bip(2-Et) 197. H A D G T L-α-Me-Phe T S D Bip(2-Et)Bip(2-Et) 198. H A D G T L-α-Me-Phe T S D Bip(2-Me) Bip(2-Et) 199. H alaE G T L-α-Me-Phe T S D Bip(2-Et) Bip(2-Me) 200. H A D G T L-α-Me-Phe T SD Bip Bip 201. H ala asp G Nle L-α-Me-Phe T S D Bip(2-Me) Bip(2-Me) 202.H ala D G nle L-α-Me-Phe T S D Bip(2-Me) Bip(2-Me) 203. H Aib D G nleL-α-Me-Phe T S D Bip(2-Me) Bip(2-Me) 204. H Aib D G Nle L-α-Me-Phe thr SD Bip(2-Me) Bip(2-Me) 205. H Aib D G Nle L-α-Me-Phe T ser D Bip(2-Me)Bip(2-Me) 206. H Aib D G Nle L-α-Me-Phe T S D Bip(2-Me) Bip 207. H G E GT F T S D Bip(2-Me) Bip(2-Me) 208. H A E G T F T S D Bip(2-Et, 4-OMe)Bip(2,4-di-Me) 209. H A E G T F T S D Bip(2-Et, 4-OMe) Bip(4-OMe) 210. HA E G T F T S D Bip(2-Et, 4-OMe) Bip(3-Me) 211. H A E G T F T S DBip(2-CH2OH, 4-OMe) Bip(2-Me) 212. H A E G T F T S D Bip(2-Me)Bip(2-Propyl, 2′-Me) 213. H A E G T F T S D Bip(2-Et, 4-OMe)Bip(2,3,4,5-tetra-Me) 214. H A E G T F T S D Bip(2-Et) Bip(2,2′-di-Me)215. H A D G T Phe(2-OMe) T S D Bip(2-Me) Bip(2-Me) 216. H A D G TPhe(2- T S D Bip(2-Me) Bip(2-Me) Hydroxy) 217. H A D G T Phe(2-Iodo) T SD Bip(2-Me) Bip(2-Me) 218. H A D G T Phe(3-OMe) T S D Bip(2-Me)Bip(2-Me) 219. H A D G T Tyr(3-Iodo) T S D Bip(2-Me) Bip(2-Me) 220. H AD G T Tyr(3-NO2) T S D Bip(2-Me) Bip(2-Me) 221. H A D G T (L)-Phe(2, T SD Bip(2-Me) Bip(2-Me) 3-di-Fluoro) 222. H A D G T Tyr(2,6-di- T S DBip(2-Me) Bip(2-Me) Me) 223. H A D G T 2- T S D Bip(2-Me) Bip(2-Me)ThienylAla 224. H A D G T (D)-Phe(2,3- T S D Bip(2-Me) Bip(2-Me)di-Fluoro) 225. H A E G T F T S D Bip(2-Et, 2′-Me) Bip(2-Et) 226. H alaD G Nle F T S D Bip(2-Et, 2′-Me) Bip(2-Me) 227. H Acc 3 D G NlePhe(penta- T S D Bip(2-Me) Bip(2-Me) Fluoro) 228. H Acc 3 D G Nle F T HD Bip(2-Me) Bip(2-Me) 229. H Acc 3 D G T Phe(penta- T H D Bip(2-Me)Bip(2-Me) Fluoro) 230. H Acc 3 D G Nle Phe(penta- T H D Bip(2-Me)Bip(2-Me) Fluoro) 231. H A D G T Phe(2- T S D Bip(2-Me) Bip(2-Me)Trifluoro methyl) 232. H A D G T Phe(2,4- T S D Bip(2-Me) Bip(2-Me)di-Chloro) 233. H 2-Abu E G T F T S D Bip(2-Me) Bip(2-Me) 234. his A aspG Nle Phe(penta- T S D Bip(2-Me) Bip(2-Me) Fluoro) 235. H A E G NlePhe(penta- T H D Bip(2-Et) Bip(2-Me) Fluoro) 236. H Aib D G T Phe(penta-T S D Bip(2-Et) Bip(2-Me) Fluoro) 237. H Aib E G Nle Phe(penta- T H DBip(2-Et) Bip(2-Me) Fluoro) 238. H A E G T Phe(2-Me) T S D Bip(2-Me)Bip(2-Me) 239. H A E G T F T S D Bip(2-Et) Bip(2-Et) 240. H A E G T F TS D Bip(2-Et, 4-OMe) Bip 241. H A E G T Phe(2- T S D Bip(2-Me) Bip(2-Me)Chloro) 242. H A E G T F T S D Bip(2-Et, 2′-Me) Bip(2,2′-di-Me) 243. H Aγ- G T F T S D Bip(2-Me) Bip(2-Me) carboxy-Glu 244. H A C G T F T S DBip(2-Me) Bip(2-Me) 245. H ala E G Nle L-α-Me-Phe T S D Bip(2-Et)Bip(2-Me) 246. H L-4-Thio E G T F T S D Bip Bip Pro 247. H A E G T F T SD Bip Bip(2,2′-di-Me) 248. H A E G T F T S D Bip(2-Me) Bip(2,2′-di-Me)249. H A E G T F T S D Bip(2′-Me) Bip(2-Me) 250. H A E G T F T S D BipBip(2′-Me) 251. H A E G T F T S D Bip(2-Me) Bip(2′-Me) 252. H A E G T FT S D Bip(2′-Me) Bip 253. H Aib E G Nle Phe(penta- T S D bip(2′-Me)Bip(2-Me) Fluoro) 254. H A E G T F T S D Bip(2′-Me) Bip(2,2′-di-Me) 255.H A E G T F T S D Bip(2′-Me) Bip(2′-Me) 256. H A E G T F T S DBip(2,2′-di-Me) Bip 257. H A E G T F T S D Bip(2,2′-di-Me) Bip(2-Me)258. H A E G T F T S D Bip(2,2′-di-Me) Bip(2-Et) 259. H A E G T F T S DBip(2,2′-di-Me) Bip(2,2′-di-Me) 260. H A E G T F T S D Bip(2-Me)Phe(4-n-Butyl) 261. H A E G T F T S D Bip(2-Me) Phe(3-Phenyl) 262. H A EG T F T S D Bip(2-Me) Phe(4-Cyclohexyl) 263. H A E G T F T S D Bip(2-Me)Phe(4-Phenoxy) 264. H A E G T F T S D Phe(4-n-Butyl) Bip(2-Me) 265. H AE G T F T S D Phe(4-Cyclohexyl) Bip(2-Me) 266. H A E G T F T S DPhe(4-Phenoxy) Bip(2-Me) 267. H A D G T Phe(3- T S D Bip(2-Me) Bip(2-Me)Fluoro) 268. H A D G T Phe(4- T S D Bip(2-Me) Bip(2-Me) Fluoro) 269. H AD G T Phe(3,4- T S D Bip(2-Me) Bip(2-Me) di-Fluoro) 270. H A D G TPhe(3,5- T S D Bip(2-Me) Bip(2-Me) di-Fluoro) 271. H A D G T Phe(3,4,5-T S D Bip(2-Me) Bip(2-Me) tri-Fluoro) 272. H ala D G Nle F T H DBip(2-Me) Bip(2-Me) 273. H ala D G T Phe(penta- T H D Bip(2-Me)Bip(2-Me) Fluoro) 274. H ala E G Nle Phe(penta- T H D Bip(2-Me)Bip(2-Me) Fluoro) 275. H A H G Nle Phe(penta- T H D Bip(2-Me) Bip(2-Me)Fluoro) 276. H A D G Nle Phe(penta- T S D Bip(2,4-di-OMe) Bip(2-Me)Fluoro) 277. H A E G T F T S D Bip(2-Me, 4-OMe) Bip(3,4- Methylenedioxy)278. H A E G T F T S D Bip(2-Et) Bip(3,4- Methylenedioxy) 279. H A D G TF T S D Bip(2,4-di-4-OMe) 4-(1-Naphthyl)-Phe 280. H A E G T F T S DBip(2-Me, 4-OMe) 4-(1-Naphthyl)-Phe 281. H A D G T F T S DBip(2,4-di-OMe) Bip(4-OMe) 282. H A E G T F T S D Bip(2-Me, 4-OMe)Bip(4-OMe) 283. H A E G T F T S D Bip(2,4-di-OMe) Bip(4-Me) 284. H A E GT F T S D Bip(2-Me, 4-OMe) Bip(4-Me) 285. H A D G T F T S DBip(2,4-di-OMe) Bip(2,4-di-OMe) 286. H A E G T F T S D Bip(2-Me, 4-OMe)Bip(2-Me, 4-OMe) 287. H A D G T F T S D Bip(2,4-di-Me) Bip(2,4-di-Me)288. H A E G T F T S D Bip(2,4-di-OMe) Bip(3-Me) 289. H A E G T F T S DBip(2-Me,4-OMe) Bip(3-Me) 290. H A 4- G T F T S D Bip(2-Me) Bip(2-Me)ThiazoylAla 291. H ala D G Nle Phe(penta- T H D Bip(2-Me) Bip(2-Me)Fluoro) 292. H A E G T F T S D Bip(2-Et, 4,5- Bip(2-Me) Methylenedioxy)293. H N—Me- E G Nle Phe(penta- T H D Bip(2-Et) Bip(2-Me) Ala Fluoro)294. H N—Me- D G Nle Phe(penta- T S D Bip(2-Me) Bip(2-Me) Ala Fluoro)295. H N—Me- D G T Phe(penta- T S D Bip(2-Me) Bip(2-Me) Ala Fluoro) 296.H N—Me- E G Nle Phe(penta- T H D Bip(2-Me) Bip(2-Me) Ala Fluoro) 297. HN—Me- E G T Phe(penta- T S D Bip(2-Me) Bip(2-Me) Ala Fluoro) 298. HSarcosyl E G T F T S D Bip(2-Me) Bip(2-Me) 299. H A E G T F T S DBip(3-CH2NH2) Bip(2-Me) 300. H A E G T F T S D Bip(2-CH2NH2) Bip(2-Me)301. H A E G T F T S D Bip(4-CH2NH2) Bip(2-Me) 302. H A E G T F T S DBip(3-CH2—COOH) Bip(2- 303. H A E G T F T S D Bip(2-Me) Bip(2′-CH2—COOH)304. H A E G T F T S D Bip(2-Me) (D,L)-Bip(2- CH2—COOH) 305. H A E G T FT S D Bip(2-Me) Bip(4-CH2—COOH) 306. H A E G T F T S D Bip(2-Me)Bip(3-CH2—COOH) 307. H A E G T F T S D Bip(2-Me) Bip(3-CH2NH2) 308. H AE G T F T S D Bip(2-Me) Bip(4-CH2NH2) 309. H A E G T F T S D Bip(2-Me)Bip(2-CH2NH2) 310. H A E G T F T S D Phe[4-(1-propargyl)] Bip(2-Me) 311.H A E G T F T S D Phe[4-(1-propenyl)] Bip(2-Me) 312. H A asp G TL-α-Me-Phe T S D Bip(2-Et) Bip(2-Me) 313. H A D G thr L-α-Me-Phe T S DBip(2-Et) Bip(2-Me) 314. H A D G T L-α-Me-Phe T S asp Bip(2-Et)Bip(2-Me) 315. H A D G T L-α-Me-Phe T S D bip(2-Et) Bip(2-Me) 316. H alaasp G T L-α-Me-Phe T S D Bip(2-Et) Bip(2-Me) 317. H Aib D G T L-α-Me-Phethr S D Bip(2-Et) Bip(2-Me) 318. H Aib D G T L-α-Me-Phe T S aspBip(2-Et) Bip(2-Me) 319. H ala D G Nle Phe(penta- T S D bip(2-Me)Bip(2-Me) Fluoro) 320. H ala D G Nle Phe(penta- T S D bip(2-Et)Bip(2-Me) Fluoro) 321. H ala D G Nle Phe(penta- T S D Bip(2-Me)bip(2-Me) Fluoro) 322. H ala D G Nle Phe(penta- T S D Bip(2-Me)bip(2-Et) Fluoro) 323. H Aib D G Nle Phe(penta- T S D bip(2-Me)Bip(2-Me) Fluoro) 324. H Aib D G Nle Phe(penta- T S D bip(2-Et)Bip(2-Me) Fluoro) 325. H Aib D G Nle Phe(penta- T S D Bip(2-Me)bip(2-Me) Fluoro) 326. H Aib D G Nle Phe(penta- T S D Bip(2-Me)bip(2-Et) Fluoro) 327. H A E G T F T S D Bip(2-Me) (D,L)-□-Me-Bip 328. HA E G T F T S D Bip (D,L)-□-Me-Bip 329. H A D G allo- L-α-Me-Phe T S DBip(2-Et) Bip(2-Me) Thr 330. H A D G T L-α-Me-Phe allo- S D Bip(2-Et)Bip(2-Me) Thr 331. H A D G T L-α-Me-Phe T hSer D Bip(2-Et) Bip(2-Me)332. H A D G T L-α-Me-Phe T T D Bip(2-Et) Bip(2-Me) 333. H A D G TL-α-Me-Phe T S E Bip(2-Et) Bip(2-Me) 334. H A E G Nle F T S D Bip(2-Et)Bip(2-Me) 335. H A asp G T L-α-Me-Phe T S D Bip(2-Et) Bip(2-Me) 336. HAib D G thr L-α-Me-Phe T S D Bip(2-Et) Bip(2-Me) 337. H Aib D G TL-α-Me-Phe thr S D Bip(2-Et) Bip(2-Me) 338. H Aib D G T L-α-Me-Phe T Sasp Bip(2-Et) Bip(2- 339. H A D G T L-α-Me-Phe T S DBip(2-Et)-NH-[2-(penta- Fluoro-phenyl)ethyl] 340. H A D G Nle L-α-Me-PheT S D Bip(2-Et)-NH-[2-(penta- Fluoro-phenyl)ethyl] 341. H Aib E G TL-α-Me-Phe T S D Bip(2-Et)-NH-[2-(penta- Fluoro-phenyl)ethyl] 342. H AibD G Nle L-α-Me-Phe T S D Bip(2-Et)-NH-[2-(penta- Fluoro-phenyl)ethyl]343. H Aib asp G T L-α-Me-Phe T S D Bip(2-Et) Bip(2-Me) 344. H ala E G TL-α-Me-Phe T S D Bip(2-Et) Bip(2-Me) 345. H ala E G T L-Phe(2,6- T S DBip(2-Et) Bip(2-Me) di-Fluoro) 346. H N—Me- E G T L-α-Me-Phe T S DBip(2-Et) Bip(2-Me) Ala 347. H A N—Me- G T L-α-Me-Phe T S D Bip(2-Et)Bip(2-Me) Glu 348. H A E N—Me- T L-α-Me-Phe T S D Bip(2-Et) Bip(2-Me)Gly 349. H A D G Nle (D,L)-α-Me- T S D Bip(2-Et,4-OMe) Bip(2-Me)Phe(penta- Fluoro) 350. H ala D G Nle (D,L)-α-Me- T S D Bip(2-Et,4-OMe)Bip(2-Me) Phe(penta- 1Fluoro) 351. H Aib D G Nle (D,L)-α-Me- T S DBip(2-Et,4-OMe) Bip(2-Me) Phe(penta- Fluoro) 352. H ala E G T D-Phe(2,6-T S D Bip(2-Et) Bip(2-Me) di-Fluoro) 353. H Aib D G T D-Phe(2,6- T S DBip(2-Et) Bip(2-Me) di-Fluoro) 354. H A E G T (D,L)-α-Me- T S DBip(2-Et,4-OMe) Bip(2-Me) Phe(penta- Fluoro) 355. H A D G T (D,L)-α-Me-T S D Bip(2-Et,4-OMe) Bip(2-Me) Phe(penta- Fluoro) 356. H ala E G T(D,L)-α-Me- T S D Bip(2-Et,4-OMe) Bip(2-Me) Phe(penta- Fluoro) 357. H AD G T L-α-Me-Phe T S D Bip(2-Et) bip(2-Et) 358. H Aib D G T L-α-Me-Phe TS D Bip(2-Et) bip(2-Me) 359. H A E G T L-α-Me-Phe T S D Bip(3-OH)Bip(2-Me) 360. H A E G T L-α-Me-Phe T S D Bip(4-OH) Bip(2-Me) 361. H A EG T L-α-Me-Phe T S D Bip(2-OEt) Bip(2-Me) 362. H A E G T L-α-Me-Phe T SD Bip(3-OEt) Bip(2-Me) 363. H A E G T L-α-Me-Phe T S D Bip(3-OCF3)Bip(2-Me) 364. H A E G T L-α-Me-Phe T S D Bip(3-NO2) Bip(2-Me) 365. H AE G T L-α-Me-Phe T S D Bip(3-CF3) Bip(2-Me) 366. H A E G T L-α-Me-Phe TS D Bip(3-F) Bip(2-Me) 367. H A E G T L-α-Me-Phe T S D Bip(3-Cl)Bip(2-Me) 368. H A E G T L-α-Me-Phe T S D Bip(3-Ph) Bip(2-Me) 369. H A EG T L-α-Me-Phe T S D Bip(3-Et) Bip(2-Me) 370. H A E G T L-α-Me-Phe T S DBip(3-i-Pr) Bip(2-Me) 371. H A E G T L-α-Me-Phe T S D Bip(4-i-Pr)Bip(2-Me) 372. H A E G T L-α-Me-Phe T S D Bip(4-Pr) Bip(2-Me) 373. H A EG T L-α-Me-Phe T S D Bip(3-Pr) Bip(2-Me) 374. H A E G T L-α-Me-Phe T S DBip(2,5-di-Cl) Bip(2-Me) 375. H A E G T L-α-Me-Phe T S D Bip(2,5-di-F)Bip(2-Me) 376. H A E G T L-α-Me-Phe T S D Bip(3,4-di-F) Bip(2-Me) 377. HA E G T L-α-Me-Phe T S D Bip(3,4-di-Cl) Bip(2-Me) 378. H A E G TL-α-Me-Phe T S D Bip(2,3-di-Cl) Bip(2-Me) 379. H A E G T L-α-Me-Phe T SD Bip(3-NHAc) Bip(2-Me) 380. H A E G T L-α-Me-Phe T S D Bip(4-NHAc)Bip(2-Me) 381. H A E G Aoc L-α-Me-Phe T S D Bip(2-Et) Bip(2-Me) 382. H AD G Nle F T S D Bip(2-Et) Bip(2-Me) 383. H ala E G T L-Phe(2- T S DBip(2-Et) Bip(2-Me) Fluoro) 384. H Aib D G Nle (D,L)-α- T S D Bip(2-Et)Bip(2-Me) Et-Phe 385. H Aib D G T L-α-Me-Phe T (D,L)- D Bip(2-Et)Bip(2-Me) α-Me- Ser 386. H A D G T (L)-α-Me- T S D Bip(2-Et,4-OMe)Bip(2-Me) (2,6-Phe di-Fluoro) 387. H A E G T L-α-Me-Phe T S DBip(4-t-Bu) Bip(2-Me) 388. H ala E G Nle (L)-α-Me- T S D Bip(2-Et,4-OMe)Bip(2-Me) Phe(2,6- di-Fluoro) 389. H ala D G Nle (L)-α-Me- T S DBip(2-Et,4-OMe) Bip(2-Me) Phe(2,6- di-Fluoro) 390. H Aib E G Nle(L)-α-Me- T S D Bip(2-Et,4-OMe) Bip(2-Me) Phe(2,6- di-Fluoro) 391. H AibD G Nle (L)-α-Me- T S D Bip(2-Et,4-OMe) Bip(2-Me) Phe(2,6- di-Fluoro)392. H A D G Nle (L)-α-Me- T S D Bip(2-Et) Bip(2-Me) Phe(2,6- di-Fluoro)393. H A D G T F T S D Bip(2-Et) Bip(2-Me)

TABLE II The peptides listed below are carboxamide at the C-terminus.SEQ ID Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa NO: A 1 2 3 4 5 6 7 8 9 Y Z394. Acetyl H A E G T F T S D Bip Bip 395. β-Ala H A E G T F T S D BipBip 396. Ahx H A E G T F T S D Bip Bip 397. D H A E G T F T S D Bip Bip398. E H A E G T F T S D Bip Bip 399. F H A E G T F T S D Bip Bip 400. GH A E G T F T S D Bip Bip 401. K H A E G T F T S D Bip Bip 402. Nva H AE G T F T S D Bip Bip 403. N H A E G T F T S D Bip Bip 404. R H A E G TF T S D Bip Bip 405. S H A E G T F T S D Bip Bip 406. T H A E G T F T SD Bip Bip 407. V H A E G T F T S D Bip Bip 408. W H A E G T F T S D BipBip 409. Y H A E G T F T S D Bip Bip 410. Caprolactam H A E G T F T S DBip Bip 411. Bip H A E G T F T S D Bip Bip 412. Ser(Bzl) H A E G T F T SD Bip Bip 413. 3-PyridylAla H A E G T F T S D Bip Bip 414. Phe(4-Me) H AE G T F T S D Bip Bip 415. Phe(pentafluoro) H A E G T F T S D Bip Bip

TABLE III

SEQ ID NO: R—CH₂— Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7 Xaa8 Xaa9 Y Z 416.4-Methylbenzyl H A E G T F T S D Bip(2-Me) Bip(2-Me) 417. 4-FluorobenzylH A E G T F T S D Bip(2-Me) Bip(2-Me) 418. Propyl H A E G T F T S DBip(2-Me) Bip(2-Me) 419. Hexyl H A E G T F T S D Bip(2-Me) Bip(2-Me)420. Cyclohexylmethyl H A E G T F T S D Bip(2-Me) Bip(2-Me) 421.6-Hydroxypentyl H A E G T F T S D Bip(2-Me) Bip(2-Me) 422.2-Thienylmethyl H A E G T F T S D Bip(2-Me) Bip(2-Me) 423.3-Thienylmethyl H A E G T F T S D Bip(2-Me) Bip(2-Me) 424.Pentafluorobenzyl H A E G T F T S D Bip(2-Me) Bip(2-Me) 425.2-Naphthylmethyl H A E G T F T S D Bip(2-Me) Bip(2-Me) 426.4-Biphenylmethyl H A E G T F T S D Bip(2-Me) Bip(2-Me) 427. 9- H A E G TF T S D Bip(2-Me) Bip(2-Me) Anthracenylmethyl 428. Benzyl H A E G T F TS D Bip(2-Me) Bip(2-Me) 429. (S)-(2-Amino-3- H A E G T F T S D Bip(2-Me)Bip(2-Me) phenyl)propyl 430. Methyl H A E G T F T S D Bip Bip 431.Benzyl- H A E G T F T S D Bip Bip 432. 2-aminoethyl H A E G T F T S DBip(2-Me) Bip(2-Me) 433. (S)-2- H A E G T F T S D Bip(2-Me) Bip(2-Me)Aminopropyl *All of the compounds in Table III were prepared asC-terminal carboxamides.

TABLE IV SEQ ID NO: Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7 Xaa8 Xaa9 Y Z B434. H A E G T F T S D Bip 2-Nal W 435. H A E G T F T S D Bip Phe(penta-2-Nal Fluoro) 436. H A E G T F T S D Bip Phe(penta- Phe(penta- Fluoro)Fluoro) 437. H A E G T F T S D Bip Phe(penta- Ser(Bzl) Fluoro) 438. H AE G T F T S D Bip Phe(penta- Phe(4- Fluoro) NO₂) 439. H A E G T F T S DBip Phe(penta- 3- Fluoro) PyridylAla 440. H A E G T F T S D BipPhe(penta- Nva Fluoro) 441. H A E G T F T S D Bip Phe(penta- K Fluoro)442. H A E G T F T S D Bip Phe(penta- D Fluoro) 443. H A E G T F T S DBip Phe(penta- S Fluoro) 444. H A E G T F T S D Bip Phe(penta- H Fluoro)445. H A E G T F T S D Bip Phe(penta- Y Fluoro) 446. H A E G T F T S DBip Phe(penta- W Fluoro) 447. H A E G T F T S D Bip Phe(penta- F Fluoro)448. H A E G T F T S D 2-Nal Phe(penta- W Fluoro) 449. H A E G T F T S DBip Bip Bip 450. H A E G T F T S D Bip Bip Nva 451. H A E G T F T S DBip(2- Bip(2-Me) ser Me) 452. H A E G T F T S D Bip(2- Bip(2-Me) Gly-OHMe) 453. H A E G T F T S D Bip(2- Bip(2-Me) β-Ala-OH Me) 454. H A E G TF T S D Bip(2- Bip(2-Me) GABA- Me) OH 455. H A E G T F T S D Bip(2-Bip(2-Me) APA-OH Me) 456. T S D Bip Bip 518. T H D Bip Bip *All of thecompounds in Table IV were prepared as C-terminal carboxamides, exceptfor those compounds marked by an asterisk, which are carboxylic acids.

EXAMPLE 12

Synthesis and testing of a peptide corresponding to the “message”sequence of GLP-1 and of the same peptide to which an “address”biphenylalanine dipeptide unit is attached at the C-terminus

The peptide corresponding to the N-terminal 1-9 sequence of GLP-1,His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-NH2, which in this invention isreferred to as the “message” sequence of GLP-1, and the GLP-1 11-merpeptide analog His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Bip-Bip-NH2, which iscomprised of the message sequence of GLP-1 and of a C-terminalbiphenylalanine dipeptide unit, were prepared using the methodsdescribed herein and tested in the cAMP cell-based assay describe inExample 13. The GLP-1 11-mer peptide analog stimulated cAMP productionin a dose-response manner corresponding to an EC₅₀ value of 1.1micromolar, determined as in Example 13. In the same assay, the EC₅₀value determined for the peptide corresponding to the “message” sequenceof GLP-1 was greater than 1 millimolar. The EC₅₀ value for GLP-1, usedin the assay as a positive control, was less than 0.100 nanomolar.

EXAMPLE 13 Cyclic AMP Determination

The GLP-1 receptor is a G-protein coupled receptor. GLP-1 (7-36)-amide,the biologically active form, binds to the GLP-1 receptor and throughsignal transduction causes activation of adenylate cyclase and raisesintracellular cAMP levels. To monitor agonism of peptide compounds instimulating the GLP-1 receptor, adenyl cyclase activity was monitored byassaying for cellular cAMP levels. Full-length human glucagon-likepeptide 1 receptor was stably expressed in CHO-K1 cells. The clones werescreened for best expression of GLP-1R and CHO-GLP-1R-19 was selected.Cells were cultured in Ham's F12 nutritional media (Gibco #11765-054),10% FBS, 1× L-Glutamine, 1× Pen/Strep, and 0.4 mg/ml G418. CHO-GLP-1R-19cells (2,500 in 100 μl of media) were plated into each well of a 96-welltissue culture microtiter plate and incubated in 5% CO₂ atmosphere at37° C., for 72 h. On the day of the assay, cells were washed once with100 μl of PBS. To cells in each well, 10 μl of compound and 90 μl ofreaction media (Phenol red free DMEM media with low glucose(Gibco#11054-020), 0.1% BSA (Sigma #A7284), 0.3 mM IBMX (3-isobutyl-1methylxanthine, Sigma #15879) were added and incubated at 37° C. for 1h. The compounds were initially screened at 1 μM and 10 μM forstimulation of cAMP. Dose dependence for compounds showing 50% ofmaximal GLP-1 (at 100 nM) activity was determined at half-logconcentrations in duplicate. After incubation, medium was removed andcells were washed once with 100 μl of PBS. Fifty μl of lysis reagent-1from the cyclic AMP SPA kit (Amersham Pharmacia Biotech, RPA 559;reagents were reconstituted according to the kit instructions) was addedinto each well. The plate was shaken at room temperature for 15 min.Twenty μl of lysate was transferred into each well of a 96-wellOptiPlate (Packard # 6005190) and 60 μl of SPA immunoreagent from thekit was added. After incubation at room temperature for 15-18 h, plateswere counted 2 min each/well in a TopCount NXT(Packard).

In each 96-well plate, GLP-1 (control), and five compounds (induplicate) were run at seven half-log doses. Ten nM GLP-1 was platedinto ten additional wells to serve as a reference standard fordetermination of maximal activity. The data obtained was processed inExcel-fit database. From a cyclic AMP standard curve, the amounts ofreleased cAMP were determined and the % maximal activity was calculatedand plotted against log compound concentration. The data was analyzed bynonlinear regression curve fit (sigmoidal dose) to determine the EC₅₀ ofthe compounds.

EXAMPLE 14 In-Vivo Studies

The in-vivo glucose lowering properties for four representative 11-merpeptides, compound A, compound B, compound C and compound D in a ratmodel is described below. Continuous intravenous infusion of compound Aand compound B significantly attenuated the postprandial glucoseexcursion curve in subcutaneous glucose tolerance test (scGTT) (see FIG.1 and FIG. 2). In addition, these two 1′-mer peptides administered bysubcutaneous injection also produced a significant glucose loweringeffect in this model (see FIG. 3 and FIG. 4). A clear dose-responserelationship was observed following both continuous intravenous infusionand subcutaneous bolus injection of the analogs for their glucoselowering effects. The significant glucose lowering effect for compound Aand compound B was observed at 12 and 120 μmol/kg/min, respectively,when the compound was administered by continuous infusion. For thesubcutaneous administration, the maximum effective doses for Compound Aand Compound B were about 2 and 20 nmol/kg, respectively.

For compounds C and D, studies using subcutaneous injection in a ratintraperitoneal glucose tolerance test (ipGTT) model showed thatsignificant glucose excursion attenuation could be achieved for bothcompounds in a dose-related fashion(see FIG. 5 and FIG. 6). FIG. 7 showsthe effects of native GLP-1 in this model.

Utility & Combinations

Utilities

The present invention provides novel GLP peptide mimics, with apreference for mimicking GLP-1, such that the compounds of the presentinvention have agonist activity for the GLP-1 receptor. Further, the GLPpeptide mimics of the present invention exhibit increased stability toproteolytic cleavage as compared to GLP-1 native sequences.

Accordingly, the compounds of the present invention can be administeredto mammals, preferably humans, for the treatment of a variety ofconditions and disorders, including, but not limited to, treating ordelaying the progression or onset of diabetes (preferably Type II,impaired glucose tolerance, insulin resistance, and diabeticcomplications, such as nephropathy, retinopathy, neuropathy andcataracts), hyperglycemia, hyperinsulinemia, hypercholesterolemia,elevated blood levels of free fatty acids or glycerol, hyperlipidemia,hypertriglyceridemia, obesity, wound healing, tissue ischemia,atherosclerosis, hypertension, AIDS, intestinal diseases (such asnecrotizing enteritis, microvillus inclusion disease or celiac disease),inflammatory bowel syndrome, chemotherapy-induced intestinal mucosalatrophy or injury, anorexia nervosa, osteoporosis, dysmetabolicsyndrome, as well as inflammatory bowel disease (such as Crohn's diseaseand ulcerative colitis). The compounds of the present invention may alsobe utilized to increase the blood levels of high density lipoprotein(HDL).

In addition, the conditions, diseases, and maladies collectivelyreferenced to as “Syndrome X” or Metabolic Syndrome as detailed inJohannsson J. Clin. Endocrinol. Metab., 82, 727-34 (1997), may betreated employing the compounds of the invention.

Combinations

The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, a therapeuticallyeffective amount of at least one of the compounds of formula I, alone orin combination with a pharmaceutical carrier or diluent. Optionally,compounds of the present invention can be used alone, in combinationwith other compounds of the invention, or in combination with one ormore other therapeutic agent(s), e.g., an antidiabetic agent or otherpharmaceutically active material.

The compounds of the present invention may be employed in combinationwith other GLP-1 peptide mimics or other suitable therapeutic agentsuseful in the treatment of the aforementioned disorders including:anti-diabetic agents; anti-hyperglycemic agents; hypolipidemic/lipidlowering agents; anti-obesity agents (including appetitesupressants/modulators) and anti-hypertensive agents. In addition, thecompounds of the present invention may be combined with one or more ofthe following therapeutic agents; infertility agents, agents fortreating polycystic ovary syndrome, agents for treating growthdisorders, agents for treating frailty, agents for treating arthritis,agents for preventing allograft rejection in transplantation, agents fortreating autoimmune diseases, anti-AIDS agents, anti-osteoporosisagents, agents for treating immunomodulatory diseases, antithromboticagents, agents for the treatment of cardiovascular disease, antibioticagents, anti-psychotic agents, agents for treating chronic inflammatorybowel disease or syndrome and/or agents for treating anorexia nervosa.

Examples of suitable anti-diabetic agents for use in combination withthe compounds of the present invention include biguanides (e.g.,metformin or phenformin), glucosidase inhibitors (e.g., acarbose ormiglitol), insulins (including insulin secretagogues or insulinsensitizers), meglitinides (e.g., repaglinide), sulfonylureas (e.g.,glimepiride, glyburide, gliclazide, chlorpropamide and glipizide),biguanide/glyburide combinations (e.g., Glucovance®), thiazolidinediones(e.g., troglitazone, rosiglitazone and pioglitazone), PPAR-alphaagonists, PPAR-gamma agonists, PPAR alpha/gamma dual agonists, glycogenphosphorylase inhibitors, inhibitors of fatty acid binding protein(aP2), DPP-IV inhibitors, and SGLT2 inhibitors.

Other suitable thiazolidinediones include Mitsubishi's MCC-555(disclosed in U.S. Pat. No. 5,594,016), Glaxo-Welcome's GL-262570,englitazone (CP-68722, Pfizer) or darglitazone (CP-86325, Pfizer,isaglitazone (MIT/J&J), JTT-501 (JPNT/P&U), L-895645 (Merck), R-119702(Sankyo/WL), NN-2344 (Dr. Reddy/NN), or YM-440 (Yamanouchi).

Suitable PPAR alpha/gamma dual agonists include AR-HO39242(Astra/Zeneca), GW-409544 (Glaxo-Wellcome), KRP297 (Kyorin Merck) aswell as those disclosed by Murakami et al., “A Novel Insulin SensitizerActs As a Coligand for Peroxisome Proliferation—Activated Receptor Alpha(PPAR alpha) and PPAR gamma. Effect on PPAR alpha Activation on AbnormalLipid Metabolism in Liver of Zucker Fatty Rats”, Diabetes 47, 1841-1847(1998), and in U.S. application Ser. No. 09/644,598, filed Sep. 18,2000, the disclosure of which is incorporated herein by reference,employing dosages as set out therein, which compounds designated aspreferred are preferred for use herein.

Suitable aP2 inhibitors include those disclosed in U.S. application Ser.No. 09/391,053, filed Sep. 7, 1999, and in U.S. application Ser. No.09/519,079, filed Mar. 6, 2000, employing dosages as set out herein.

Suitable DPP4 inhibitors that may be used in combination with thecompounds of the invention include those disclosed in WO99/38501,WO99/46272, WO99/67279 (PROBIODRUG), WO99/67278 (PROBIODRUG), WO99/61431(PROBIODRUG), NVP-DPP728A(1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine)(Novartis) as disclosed by Hughes et al., Biochemistry, 38(36),11597-11603, 1999, TSL-225(tryptophyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (disclosedby Yamada et al., Bioorg. & Med. Chem. Lett. 8 (1998) 1537-1540,2-cyanopyrrolidides and 4-cyanopyrrolidides, as disclosed by Ashworth etal., Bioorg. & Med. Chem. Lett., Vol. 6, No. 22, pp 1163-1166 and2745-2748 (1996) employing dosages as set out in the above references.

Suitable meglitinides include nateglinide (Novartis) or KAD1229(PF/Kissei).

Examples of other suitable glucagon-like peptide-1 (GLP-1,) compoundsthat may be used in combination with the GLP-1 mimics of the presentinvention include GLP-1 (1-36) amide, GLP1 (7-36) amide, GLP1 (7-37) (asdisclosed in U.S. Pat. No. 5,614,492 to Habener), as well as AC2993(Amylin), LY-315902 (Lilly) and NN-2211 (NovoNordisk).

Examples of suitable hypolipidemic/lipid lowering agents for use incombination with the compounds of the present invention include one ormore MTP inhibitors, HMG CoA reductase inhibitors, squalene synthetaseinhibitors, fibric acid derivatives, ACAT inhibitors, lipoxygenaseinhibitors, cholesterol absorption inhibitors, ileal Na⁺/bile acidcotransporter inhibitors, upregulators of LDL receptor activity, bileacid sequestrants, cholesterol ester transfer protein inhibitors (e.g.,CP-529414 (Pfizer)) and/or nicotinic acid and derivatives thereof.

MTP inhibitors which may be employed as described above include thosedisclosed in U.S. Pat. No. 5,595,872, U.S. Pat. No. 5,739,135, U.S. Pat.No. 5,712,279, U.S. Pat. No. 5,760,246, U.S. Pat. No. 5,827,875, U.S.Pat. No. 5,885,983 and U.S. Pat. No. 5,962,440.

The HMG CoA reductase inhibitors which may be employed in combinationwith one or more compounds of formula I include mevastatin and relatedcompounds, as disclosed in U.S. Pat. No. 3,983,140, lovastatin(mevinolin) and related compounds, as disclosed in U.S. Pat. No.4,231,938, pravastatin and related compounds, such as disclosed in U.S.Pat. No. 4,346,227, simvastatin and related compounds, as disclosed inU.S. Pat. Nos. 4,448,784 and 4,450,171. Other HMG CoA reductaseinhibitors which may be employed herein include, but are not limited to,fluvastatin, disclosed in U.S. Pat. No. 5,354,772, cerivastatin, asdisclosed in U.S. Pat. Nos. 5,006,530 and 5,177,080, atorvastatin, asdisclosed in U.S. Pat. Nos. 4,681,893, 5,273,995, 5,385,929 and5,686,104, atavastatin (Nissan/Sankyo's nisvastatin (NK-104)), asdisclosed in U.S. Pat. No. 5,011,930, visastatin (Shionogi-Astra/Zeneca(ZD-4522)), as disclosed in U.S. Pat. No. 5,260,440, and related statincompounds disclosed in U.S. Pat. No. 5,753,675, pyrazole analogs ofmevalonolactone derivatives, as disclosed in U.S. Pat. No. 4,613,610,indene analogs of mevalonolactone derivatives, as disclosed in PCTapplication WO 86/03488,6-[2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and derivativesthereof, as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a3-substituted pentanedioic acid derivative) dichloroacetate, imidazoleanalogs of mevalonolactone, as disclosed in PCT application WO86/07054,3-carboxy-2-hydroxy-propane-phosphonic acid derivatives, asdisclosed in French Patent No. 2,596,393, 2,3-disubstituted pyrrole,furan and thiophene derivatives, as disclosed in European PatentApplication No. 0221025, naphthyl analogs of mevalonolactone, asdisclosed in U.S. Pat. No. 4,686,237, octahydronaphthalenes, such asdisclosed in U.S. Pat. No. 4,499,289, keto analogs of mevinolin(lovastatin), as disclosed in European Patent Application No. 0142146A2, and quinoline and pyridine derivatives, as disclosed in U.S. Pat.Nos. 5,506,219 and 5,691,322.

Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin,atorvastatin, fluvastatin, cerivastatin, atavastatin and ZD-4522.

In addition, phosphinic acid compounds useful in inhibiting HMG CoAreductase, such as those disclosed in GB 2205837, are suitable for usein combination with the compounds of the present invention.

The squalene synthetase inhibitors suitable for use herein include, butare not limited to, α-phosphono-sulfonates disclosed in U.S. Pat. No.5,712,396, those disclosed by Biller et al., J. Med. Chem., 1988, Vol.31, No. 10, pp 1869-1871, including isoprenoid(phosphinyl-methyl)phosphonates, as well as other known squalenesynthetase inhibitors, for example, as disclosed in U.S. Pat. Nos.4,871,721 and 4,924,024 and in Biller, S. A., Neuenschwander, K.,Ponpipom, M. M., and Poulter, C. D., Current Pharmaceutical Design, 2,1-40 (1996).

In addition, other squalene synthetase inhibitors suitable for useherein include the terpenoid pyrophosphates disclosed by P. Ortiz deMontellano et al., J. Med. Chem., 1977, 20, 243-249, the farnesyldiphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs asdisclosed by Corey and Volante, J. Am. Chem. Soc., 1976, 98, 1291-1293,phosphinylphosphonates reported by McClard, R. W. et al., J.A.C.S.,1987, 109, 5544 and cyclopropanes reported by Capson, T. L., PhDdissertation, June, 1987, Dept. Med. Chem. U of Utah, Abstract, Table ofContents, pp 16, 17, 40-43, 48-51, Summary.

The fibric acid derivatives which may be employed in combination withone or more compounds of formula I include fenofibrate, gemfibrozil,clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like,probucol, and related compounds, as disclosed in U.S. Pat. No.3,674,836, probucol and gemfibrozil being preferred, bile acidsequestrants, such as cholestyramine, colestipol and DEAE-Sephadex(Secholex®, Policexide®), as well as lipostabil (Rhone-Poulenc), EisaiE-5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402),tetrahydrolipstatin (THL), istigmastanylphos-phorylcholine (SPC, Roche),aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulenederivative), melinamide (Sumitomo), Sandoz 58-035, American CyanamidCL-277,082 and CL-283,546 (disubstituted urea derivatives), nicotinicacid, acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin,poly(diallylmethylamine) derivatives, such as disclosed in U.S. Pat. No.4,759,923, quaternary amine poly(diallyldimethylammonium chloride) andionenes, such as disclosed in U.S. Pat. No. 4,027,009, and other knownserum cholesterol lowering agents.

The ACAT inhibitor which may be employed in combination with one or morecompounds of formula I include those disclosed in Drugs of the Future24, 9-15 (1999), (Avasimibe); “The ACAT inhibitor, C1-1011 is effectivein the prevention and regression of aortic fatty streak area inhamsters”, Nicolosi et al., Atherosclerosis (Shannon, Irel). (1998),137(1), 77-85; “The pharmacological profile of FCE 27677: a novel ACATinhibitor with potent hypolipidemic activity mediated by selectivesuppression of the hepatic secretion of ApoB100-containing lipoprotein”,Ghiselli, Giancarlo, Cardiovasc. Drug Rev. (1998), 16(1), 16-30; “RP73163: a bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor”,Smith, C., et al., Bioorg. Med. Chem. Lett. (1996), 6(1), 47-50; “ACATinhibitors: physiologic mechanisms for hypolipidemic andanti-atherosclerotic activities in experimental animals”, Krause et al.,Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A.,Inflammation: Mediators Pathways (1995), 173-98, Publisher: CRC, BocaRaton, Fla.; “ACAT inhibitors: potential anti-atherosclerotic agents”,Sliskovic et al., Curr. Med. Chem. (1994), 1(3), 204-25; “Inhibitors ofacyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemicagents. 6. The first water-soluble ACAT inhibitor with lipid-regulatingactivity. Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 7.Development of a series of substitutedN-phenyl-N′-[(1-phenylcyclopentyl)methyl]ureas with enhancedhypocholesterolemic activity”, Stout et al., Chemtracts: Org. Chem.(1995), 8(6), 359-62, or TS-962 (Taisho Pharmaceutical Co. Ltd).

The hypolipidemic agent may be an upregulator of LD2 receptor activity,such as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly).

Examples of suitable cholesterol absorption inhibitor for use incombination with the compounds of the invention include SCH48461(Schering-Plough), as well as those disclosed in Atherosclerosis 115,45-63 (1995) and J. Med. Chem. 41, 973 (1998).

Examples of suitable ileal Na⁺/bile acid cotransporter inhibitors foruse in combination with the compounds of the invention include compoundsas disclosed in Drugs of the Future, 24, 425-430 (1999).

The lipoxygenase inhibitors which may be employed in combination withone or more compounds of formula I include 15-lipoxygenase (15-LO)inhibitors, such as benzimidazole derivatives, as disclosed in WO97/12615, 15-LO inhibitors, as disclosed in WO 97/12613, isothiazolones,as disclosed in WO 96/38144, and 15-LO inhibitors, as disclosed bySendobry et al., “Attenuation of diet-induced atherosclerosis in rabbitswith a highly selective 15-lipoxygenase inhibitor lacking significantantioxidant properties”, Brit. J. Pharmacology (1997) 120, 1199-1206,and Cornicelli et al., “15-Lipoxygenase and its Inhibition: A NovelTherapeutic Target for Vascular Disease”, Current Pharmaceutical Design,1999, 5, 11-20.

Examples of suitable anti-hypertensive agents for use in combinationwith the compounds of the present invention include beta adrenergicblockers, calcium channel blockers (L-type and T-type; e.g. diltiazem,verapamil, nifedipine, amlodipine and mybefradil), diuretics (e.g.,chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone,furosemide, musolimine, bumetanide, triamtrenene, amiloride,spironolactone), renin inhibitors, ACE inhibitors (e.g., captopril,zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril,pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists(e.g., losartan, irbesartan, valsartan), ET receptor antagonists (e.g.,sitaxsentan, atrsentan and compounds disclosed in U.S. Pat. Nos.5,612,359 and 6,043,265), Dual ET/AII antagonist (e.g., compoundsdisclosed in WO 00/01389), neutral endopeptidase (NEP) inhibitors,vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilatand gemopatrilat), and nitrates.

Examples of suitable anti-obesity agents for use in combination with thecompounds of the present invention include a NPY receptor antagonist, aMCH antagonist, a GHSR antagonist, a CRH antagonist, a beta 3 adrenergicagonist, a lipase inhibitor, a serotonin (and dopamine) reuptakeinhibitor, a thyroid receptor beta drug and/or an anorectic agent.

The beta 3 adrenergic agonists which may be optionally employed incombination with compounds of the present invention include AJ9677(Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer,) or otherknown beta 3 agonists, as disclosed in U.S. Pat. Nos. 5,541,204,5,770,615, 5,491,134, 5,776,983 and 5,488,064, with AJ9677, L750,355 andCP331648 being preferred.

Examples of lipase inhibitors which may be optionally employed incombination with compounds of the present invention include orlistat orATL-962 (Alizyme), with orlistat being preferred.

The serotonin (and dopamine) reuptake inhibitor which may be optionallyemployed in combination with a compound of formula I may be sibutramine,topiramate (Johnson & Johnson) or axokine (Regeneron), with sibutramineand topiramate being preferred.

Examples of thyroid receptor beta compounds which may be optionallyemployed in combination with compounds of the present invention includethyroid receptor ligands, such as those disclosed in WO97/21993 (U. CalSF), WO99/00353 (KaroBio) and GB98/284425 (KaroBio), with compounds ofthe KaroBio applications being preferred.

The anorectic agent which may be optionally employed in combination withcompounds of the present invention include dexamphetamine, phentermine,phenylpropanolamine or mazindol, with dexamphetamine being preferred.

Examples of suitable anti-psychotic agents include clozapine,haloperidol, olanzapine (Zyprexa®), Prozac® and aripiprazole (Abilify®).

The aforementioned patents and patent applications are incorporatedherein by reference.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention may be used, for example, inthose amounts indicated in the Physician's Desk Reference, as in thepatents set out above or as otherwise determined by one of ordinaryskill in the art.

Dosage and Formulation

A suitable GLP-1 peptide mimic can be administered to patients to treatdiabetes and other related diseases as the compound alone and or mixedwith an acceptable carrier in the form of pharmaceutical formulations.Those skilled in the art of treating diabetes can easily determine thedosage and route of administration of the compound to mammals, includinghumans, in need of such treatment. The route of administration mayinclude but is not limited to oral, intraoral, rectal, transdermal,buccal, intranasal, pulmonary, subcutaneous, intramuscular, intradermal,sublingual, intracolonic, intraoccular, intravenous, or intestinaladministration. The compound is formulated according to the route ofadministration based on acceptable pharmacy practice (Fingl et al., inThe Pharmacological Basis of Therapeutics, Ch. 1, p. 1, 1975;Remington's Pharmaceutical Sciences, 18^(th) ed., Mack Publishing Co,Easton, Pa., 1990).

The pharmaceutically acceptable GLP-1 peptide mimic composition of thepresent invention can be administered in multiple dosage forms such astablets, capsules (each of which includes sustained release or timedrelease formulations), pills, powders, granules, elixirs, in situ gels,microspheres, crystalline compleses, liposomes, micro-emulsions,tinctures, suspensions, syrups, aerosol sprays and emulsions. Thecomposition of the present invention can also be administered in oral,intravenous (bolus or infusion), intraperitoneal, subcutaneous,transdermally or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. The compositionmay be administered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the composition of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the disease state.

By way of general guidance, the daily oral dosage of the activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about0.6 to 20 mg/kg/day. Intravenously, the daily dosage of the activeingredient when used for the indicated effects will range between 0.001ng to 100.0 ng per min/per Kg of body weight during a constant rateinfusion. Such constant intravenous infusion can be preferablyadministered at a rate of 0.01 ng to 50 ng per min per Kg body weightand most preferably at 0.1 ng to 10.0 mg per min per Kg body weight. Thecomposition of this invention may be administered in a single dailydose, or the total daily dosage may be administered in divided doses oftwo, three, or four times daily. The composition of this invention mayalso be administered by a depot formulation that will allow sustainedrelease of the drug over a period of days/weeks/months as desired.

The composition of this invention can be administered in intranasal formvia topical use of suitable intranasal vehicles, or via transdermalroutes, using transdermal skin patches. When administered in the form ofa transdermal delivery system, the dosage administration will, ofcourse, be continuous rather than intermittent throughout the dosageregimen.

The composition is typically administered in a mixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, that is, oral tablets, capsules,elixirs, aerosol sprays generated with or without propallant and syrups,and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as but notlimited to, lactose, starch, sucrose, glucose, methyl cellulose,magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, andsorbitol; for oral administration in liquid form, the oral drugcomponents can be combined with any oral, non-toxic, pharmaceuticallyacceptable inert carrier such as, but not limited to, ethanol, glycerol,and water. Moreover, when desired or necessary, suitable binders,lubricants, disintegrating agents, and coloring agents can also beincorporated into the mixture. Suitable binders include, but not limitedto, starch, gelatin, natural sugars such as, but not limited to, glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, and waxes. Lubricants used in these dosage formsinclude sodium oleate, sodium stearate, magnesium stearate, sodiumbenzoate, sodium acetate, and sodium chloride. Disintegrants include,but are not limited to, starch, methyl cellulose, agar, bentonite, andxanthan gum.

The composition of the present invention may also be administered in theform of mixed micellar or liposome delivery systems, such as smallunilamellar vesicles, large unilamellar vesicles, and multilamellarvesicles. Liposomes can be formed from a variety of phospholipids, suchas cholesterol, stearylamine, or phosphatidylcholines. Permeationenhancers may be added to enhance drug absorption.

Since prodrugs are known to enhance numerous desirable qualities ofpharmaceuticals (i.e., solubility, bioavailability, manufacturing, etc.)the compounds of the present invention may be delivered in prodrug form.Thus, the present invention is intended to cover prodrugs of thepresently claimed compounds, methods of delivering the same andcompositions containing the same.

The compositions of the present invention may also be coupled withsoluble polymers as targetable drug carriers. Such polymers can includepolyvinyl-pyrrolidone, pyran copolymer,polyhydroxypropyl-methacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the composition of thepresent invention may be combined with a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 0.1 milligram to about 500 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.5-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivative, magnesiumstearate, and stearic acid. Similar diluents can be used to makecompressed tablets. Both tablets and capsules can be manufactured assustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solution for parenteral administration preferably contains awater-soluble salt of the active ingredient, suitable stabilizingagents, and if necessary, buffer substances. Antioxidizing agents suchas sodium bisulfite, sodium sulfite, or ascorbic acid, either alone orcombined, are suitable stabilizing agents. Also used are citric acid andits salts and sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington: The Scienceand Practice of Pharmacy, Nineteenth Edition, Mack Publishing Company,1995, a standard reference text in this field

Representative useful pharmaceutical dosage forms for administration ofthe compound of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standardtwo-piece hard gelatin capsules with 100 milligrams of powdered activeingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestable oil such as soybean oil,cottonseed oil or olive oil may be prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules shouldbe washed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosageunit, for example is 100 milligrams of active ingredient, 0.2 milligramsof colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275milligrams of microcrystalline cellulose, 11 milligrams of starch and98.8 milligrams of lactose. Appropriate coatings may be applied toincrease palatability or delay absorption.

Injectable

A parenteral composition suitable for administration by injection may beprepared by stirring for example, 1.5% by weight of active ingredient in10% by volume propylene glycol and water. The solution should be madeisotonic with sodium chloride and sterilized.

Suspension

An aqueous suspension can be prepared for oral and/or parenteraladministration so that, for example, each 5 mL contains 100 mg of finelydivided active ingredient, 20 mg of sodium carboxymethyl cellulose, 5 mgof sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mL ofvanillin or other palatable flavoring.

Biodegradable Microparticles

A sustained-release parenteral composition suitable for administrationby injection may be prepared, for example, by dissolving a suitablebiodegradable polymer in a solvent, adding to the polymer solution theactive agent to be incorporated, and removing the solvent from thematrix thereby forming the matrix of the polymer with the active agentdistributed throughout the matrix.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeunderstood that within the scope of the appended claims, the inventionmay be practiced otherwise than as specifically described herein.

The present invention is not to be limited in scope by the specificembodiments described that are intended as single illustrations ofindividual aspects of the invention. Functionally equivalent methods andcomponents in addition to those shown and described herein will becomeapparent to those skilled in the art from the foregoing description andaccompanying drawings. Such modifications are intended to fall withinthe scope of the appended claims.

1. An isolated polypeptide having a sequence of Formula IA-X_(aa1)-X_(aa2)-X_(aa3)-X_(aa4)-X_(aa5)-X_(aa6)-X_(aa7)-X_(aa8)-X_(aa9)-Y-Z-B  Iwherein, X_(aa1-9) is a naturally or nonnaturally occurring amino acidresidue; Y and Z are amino acid residues; wherein one of thesubstitutions at the alpha-carbon atoms of Y and Z may eachindependently be substituted with a primary substituent group selectedfrom the group consisting of hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl,heterocyclylalkyl said primary substituent optionally being substitutedwith a secondary substituent selected from a cycloalkyl, heterocyclyl,aryl or heteroaryl group; any of said primary or secondary substituentsmay further be substituted with one or more of, hydrogen, alkyl,cycloalkyl, arylalkyl, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl,halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido,guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl,acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy,heterocycleoxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl,mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl,guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl orphosphonic group; wherein, the primary or secondary substitutents mayoptionally be bridged by covalent bonds to form one or more fused cyclicor heterocyclic systems with each other; wherein, the other substitutionat the alpha-carbon of Y may be substituted with hydrogen, alkyl,aminoalkyl, hydroxyalkyl or carboxyalkyl; wherein, the othersubstitution at the alpha-carbon of Z may be substituted with hydrogen,alkyl, aminoalkyl, hydroxyalkyl or carboxyalkyl; A and B are optionallypresent; wherein A is present and A is hydrogen, an amino acid orpeptide containing from about 1 to about 15 amino acid residues, an Rgroup, an R—C(O) (amide) group, a carbamate group RO—C(O), a ureaR₄R₅N—C(O), a sulfonamido R—SO₂, or a R₄R₅N—SO₂; wherein R is selectedfrom the group consisting of hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl,arylalkyl, aryloxyalkyl, heteroarylalkyl and heteroaryloxyalkyl; whereinR₄ and R₅ are each independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl,heteroarylalkyl and heteroaryloxyalky; wherein the alpha-amino group ofX_(aa1) is substituted with a hydrogen or an alkyl group, said alkylgroup may optionally form a ring with A; wherein B is present and B isOR₁, NR₁R₂, or an amino acid or peptide containing from 1 to 15 aminoacid residues, terminating at the C-terminus as a carboxamide,substituted carboxamide, an ester, a free carboxylic acid or anamino-alcohol; wherein R₁ and R₂ are independently chosen from hydrogen,alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl,aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl orheteroaryloxyalkyl.
 2. The isolated polypeptide of claim 1 wherein thesubstitutions made at the alpha-carbon atoms of Y and Z are selectedfrom the group consisting of heteroarylarylmethyl, arylheteroarylmethylor biphenylmethyl forming biphenylalanine residues, any of which is alsooptionally substituted with one or more, hydrogen, alkyl, cycloalkyl,arylalkyl, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl, halo,hydroxy, mercapto, nitro, cyano, amino, acylamino, azido, guanidino,amidino, carboxyl, carboxamido, carboxamido alkyl, formyl, acyl,carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy,heterocycleoxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl,mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl,guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl andphosphonic group.
 3. The isolated polypeptide of claim 1 wherein B is anamino acid or peptide containing 1 to about 10 amino acid residues. 4.The isolated polypeptide of claim 3 wherein B is an amino acid orpeptide containing 1 to about 5 amino acid residues.
 5. The isolatedpolypeptide of claim 1 wherein X_(aa1), X_(aa2) and X_(aa3) are N—H orN-alkylated amino acid residues.
 6. The isolated polypeptide of claim 5wherein X_(aa1), X_(aa2) and X_(aa3) are N—H or N-methylated amino acidresidues.
 7. The isolated polypeptide of claim 1 wherein the othersubstitution at the alpha-carbon of Y is substituted with hydrogen,methyl or ethyl; and wherein, the other substitution at the alpha-carbonof Z is substituted with hydrogen, methyl or ethyl.
 8. The isolatedpolypeptide of claim 1 wherein X_(aa1) is naturally or nonnaturallyoccurring amino acid residue in which one of the substitutions at thealpha-carbon is a primary substituent selected from the group consistingof heterocyclylalkyl, heteroaryl, heteroarylalkyl and arylalkyl, saidprimary substituent optionally being substituted with secondarysubstituent selected from heteroaryl or heterocyclyl; and in which theother substitution at the alpha-carbon is hydrogen or alkyl; X_(aa2) isnaturally or nonnaturally occurring amino acid residue in which one ofthe substitutions at the alpha-carbon is an alkyl or cycloalkyl wherethe alkyl group may optionally form a ring with the nitrogen of X_(aa2);and wherein the other substitution at the alpha-carbon is hydrogen oralkyl; X_(aa3) is a naturally or nonnaturally occurring amino acidresidue in which one of the substitutions at the alpha-carbon isselected from the group consisting of a carboxyalkyl, bis-carboxyalkyl,sulfonylalkyl, heteroalkyl and mercaptoalkyl; and wherein the othersubstitution at the alpha-carbon is hydrogen or alkyl; X_(aa4) is anaturally or nonnaturally occurring amino acid residue in which thealpha-carbon is not substituted, or in which one of the substitutions atthe alpha-carbon is selected from the group consisting of aminoalkyl,carboxyalkyl heteroarylalkyl and heterocycylalkyl; X_(aa5) is anaturally or nonnaturally occurring amino acid residue in which one ofthe substitutions at the alpha-carbon is an alkyl or hydroxyalkyl, andin which the other substitution at the alpha-carbon is hydrogen oralkyl; X_(aa6) is a naturally or nonnaturally occurring amino acidresidue in which one of the substitutions at the alpha-carbon isselected from the group consisting of alkyl, aryl, heteroaryl,heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl andheteroarylalkyl group, and wherein the other substitution at thealpha-carbon is hydrogen or alkyl; X_(aa7) is a naturally ornonnaturally occurring amino acid residue in which one of thesubstitutions at the alpha-carbon is a hydroxylalkyl group; X_(aa8) is anaturally or nonnaturally occurring amino acid residue in which one ofthe substitutions at the alpha-carbon is selected from the groupconsisting of alkyl, hydroxylalkyl, heteroarylalkyl andcarboxamidoalkyl, and in which the other substitution at thealpha-carbon is hydrogen or alkyl; X_(aa9) is a naturally ornonnaturally occurring amino acid residue in which one of thesubstitutions at alpha-carbon is selected from the group consisting ofcarboxylalkyl, bis-carboxylalkyl, carboxylaryl, sulfonylalkyl,carboxylamidoalkyl and heteroarylalkyl; and wherein A is hydrogen, anamino acid or peptide containing from about 1 to about 5 amino acidresidues, an R group, an R—C(O) amide group, a carbamate group RO—C(O),a urea R₄R₅N—C(O), a sulfonamido R—SO₂ or a R₄R₅N—SO₂.
 9. The isolatedpolypeptide of claim 8 wherein X_(aa1) is an amino acid residue selectedfrom the group consisting of L-His, D-His, L-N-Methyl-His,D-N-Methyl-His, L-4-ThiazolylAla and D-4-ThiazolylAla; X_(aa2) is anamino acid residue selected from the group consisting of L-Ala, D-Ala,L-Pro, Gly, D-Ser, D-Asn, L-N-Methyl-Ala, D-N-Methyl-Ala, L-4-ThioPro,L-Pro(t-4-OH), L-2-Pip, L-2-Azt, Aib, S— or R-Iva and Acc₃; X_(aa3) isan amino acid residue selected from the group consisting of L-Glu,L-N-Methyl-Glu, L-Asp, D-Asp, L-His, L-Gla, L-Adp, L-Cys andL-4-ThiazolylAla; X_(aa4) is an amino acid residue selected from thegroup consisting of Gly, L-His, L-Lys and L-Asp; X_(aa5) is an aminoacid residue selected from the group consisting of L-Thr, D-Thr, L-Nle,L-Met, L-Nva and L-Aoc; X_(aa6) is an amino acid residue selected fromthe group consisting of L-Phe, L-Tyr, L-Tyr(Bzl), Tyr(3-NO₂), L-Nle,L-Trp, L-Phe(penta-Fluoro), D-Phe(penta-Fluoro), Phe(2-Fluoro),Phe(3-Fluoro), Phe(4-Fluoro), Phe(2,3-di-Fluoro), Phe(3,4-di-Fluoro),Phe(3,5-di-Fluoro), L-Phe(2,6-di-Fluoro), Phe(3,4,5-tri-Fluoro),Phe(2-Iodo), Phe(2-OH), Phe(2-OMethyl), Phe(3-OMethyl), Phe(3-Cyano),Phe(2-Chloro), Phe(2-NH₂), Phe(3-NH₂), Phe(4-NH₂), Phe(4-NO₂),Phe(4-Methyl), Phe(4-Allyl), Phe(n-butyl), Phe(4-Cyclohexyl),Phe(4-Cyclohexyloxy), Phe(4-Phenyloxy), 2-NaphthylAla, 2-PyridylAla,L-4-ThiazolylAla, L-2-Thi, L-α-Me-Phe, D-α-Me-Phe, L-α-Et-Phe,D-α-Et-Phe, L-α-Me-Phe(2-Fluoro), D-α-Me-Phe(2-Fluoro),L-α-Me-Phe(2,3-di-Fluoro), D-α-Me-Phe(2,3-di-Fluoro),L-α-Me-Phe(2,6-di-Fluoro), D-α-Me-Phe(2,6-di-Fluoro),L-α-Me-Phe(penta-Fluoro) and D-α-Me-Phe(penta-Fluoro); X_(aa7) is anamino acid residue selected from the group consisting of L-Thr, D-Thr,L-Ser and L-hSer; X_(aa8) is an amino acid residue selected from thegroup consisting of L-Ser, L-hSer, L-His, L-Asn and L-α-Me-Ser; andX_(aa9) is an amino acid residue selected from the group consisting ofL-Asp, L-Glu, L-Gla, L-Adp, L-Asn and L-His.
 10. The isolatedpolypeptide of claim 1 wherein Y is selected from the group consistingof L-Bip, D-Bip, L-Bip(2-Me), D-Bip(2-Me), L-Bip(2′-Me), L-Bip(2-Et),D-Bip(2-Et), L-Bip(3-Et), L-Bip(4-Et), L-Bip(2-n-Propyl),L-Bip(2-n-Propyl, 4-OMe), L-Bip(2-n-Propyl,2′-Me), L-Bip(3-Me),L-Bip(4-Me), L-Bip(2,3-di-Me), L-Bip(2,4-di-Me), L-Bip(2,6-di-Me),L-Bip(2,4-di-Et), L-Bip(2-Me, 2′-Me), L-Bip(2-Et, 2′-Me), L-Bip(2-Et,2′-Et), L-Bip(2-Me,4-OMe), L-Bip(2-Et,4-OMe), D-Bip(2-Et, 4-OMe),L-Bip(3-OMe), L-Bip(4-OMe), L-Bip(2,4,6-tri-Me), L-Bip(2,3-di-OMe),L-Bip(2,4-di-OMe), L-Bip(2,5-di-OMe), L-Bip(3,4-di-OMe),L-Bip(2-Et,4,5-di-OMe), L-Bip(3,4-Methylene-di-oxy), L-Bip(2-Et,4,5-Methylene-di-oxy), L-Bip(2-CH₂OH, 4-OMe), L-Bip(2-Ac),L-Bip(3-NH-Ac), L-Bip(4-NH-Ac), L-Bip(2,3-di-Chloro),L-Bip(2,4-di-Chloro), L-Bip(2,5-di-Chloro), L-Bip(3,4-di-Chloro),L-Bip(4-Fluoro), L-Bip(3,4-di-Fluoro), L-Bip(2,5-di-Fluoro),L-Bip(3-n-Propyl), L-Bip(4-n-Propyl), L-Bip(2-iso-Propyl),L-Bip(3-iso-Propyl), L-Bip(4-iso-Propyl), L-Bip(4-tert-Butyl),L-Bip(3-Phenyl), L-Bip(2-Chloro), L-Bip(3-Chloro), L-Bip(2-Fluoro),L-Bip(3-Fluoro), L-Bip(2-CF₃), L-Bip(3-CF₃), L-Bip(4-CF₃), L-Bip(3-NO₂),L-Bip(3-OCF₃), L-Bip(4-OCF₃), L-Bip(2-OEt), L-Bip(3-OEt), L-Bip(4-OEt),L-Bip(4-SMe), L-Bip(2-OH), L-Bip(3-OH), L-Bip(4-OH), L-Bip(2-CH₂—COOH),L-Bip(3-CH₂—COOH), L-Bip(4-CH₂—COOH), L-Bip(2-CH₂—NH₂),L-Bip(3-CH₂—NH₂), L-Bip(4-CH₂—NH₂), L-Bip(2-CH₂—OH), L-Bip(3-CH₂—OH),L-Bip(4-CH₂—OH), L-Phe[4-(1-propargyl)], L-Phe[4-(1-propenyl)],L-Phe[4-n-Butyl], L-Phe[4-Cyclohexyl], Phe(4-Phenyloxy),L-Phe(penta-Fluoro), L-2-(9,10-Dihydrophenanthrenyl)-Ala,4-(2-Benzo(b)furan)-Phe, 4-(4-Dibenzofuran)-Phe, 4-(4-Phenoxathiin)-Phe,4-(2-Benzo(b)thiophene)-Phe, 4-(3-thiophene)-Phe, 4-(3-Quinoline)-Phe,4-(2-Naphthyl)-Phe, 4-(1-Naphthyl)-Phe,4-(4-(3,5-dimethylisoxazole))-Phe, 4-(2,4-dimethoxypyrimidine)-Phe,homoPhe, Tyr(Bzl), Phe(3,4-di-Chloro), Phe(4-Iodo), 2-Naphthyl-Ala,L-α-Me-Bip and D-α-Me-Bip; Z is selected from the group consisting ofL-Bip, D-Bip, L-Bip(2-Me), D-Bip(2-Me), L-Bip(2′-Me), L-Bip(2-Et),D-Bip(2-Et), L-Bip(3-Me), L-Bip(4-Me), L-Bip(3-OMe), L-Bip(4-OMe),L-Bip(4-Et), L-Bip(2-n-Propyl,2′-Me), L-Bip(2,4-di-Me), L-Bip(2-Me,2′-Me), L-Bip(2-Me,4-OMe), L-Bip(2-Et,4-OMe), D-Bip(2-Et,4-OMe),L-Bip(2,6-di-Me), L-Bip(2,4,6-tri-Me), L-Bip(2,3,4,5,-tetra-Me),L-Bip(3,4-di-OMe), L-Bip(2,5-di-OMe), L-Bip(3,4-Methylene-di-oxy),L-Bip(3-NH-Ac), L-Bip(2-iso-Propyl), L-Bip(4-iso-Propyl),L-Bip(2-Phenyl), L-Bip(4-Phenyl), L-Bip(2-Fluoro), L-Bip(4-CF₃),L-Bip(4-OCF₃), L-Bip(2-OEt), L-Bip(4-OEt), L-Bip(4-SMe),L-Bip(2-CH₂—COOH), D-Bip(2-CH₂—COOH), L-Bip(2′-CH₂—COOH),L-Bip(3-CH₂—COOH), L-Bip(4-CH₂—COOH), L-Bip(2-CH₂—NH₂),L-Bip(3-CH₂—NH₂), L-Bip(4-CH₂—NH₂), L-Bip(2-CH₂—OH), L-Bip(3-CH₂—OH),L-Bip(4-CH₂—OH), L-Phe(3-Phenyl), L-Phe[4-n-Butyl], L-Phe[4-Cyclohexyl],Phe(4-Phenyloxy), L-Phe(penta-Fluoro),L-2-(9,10-Dihydrophenanthrenyl)-Ala, 4-(3-Pyridyl)-Phe,4-(2-Naphthyl)-Phe, 4-(1-Naphthyl)-Phe, 2-Naphthyl-Ala, 2-Fluorenyl-Ala,L-α-Me-Bip, D-α-Me-Bip, L-Phe(4-NO₂) and L-Phe(4-Iodo); A is selectedfrom the group consisting of H, Acetyl, β-Ala, Ahx, Gly, Asp, Glu, Phe,Lys, Nva, Asn, Arg, Ser, Thr, Val, Trp, Tyr, Caprolactam, L-Bip,L-Ser(Bzl), 3-PyridylAla, Phe(4-Me), Phe(penta-Fluoro), 4-Methylbenzyl,4-Fluorobenzyl, n-propyl, n-hexyl, cyclohexylmethyl, 6-hydroxypentyl,2-Thienylmethyl, 3-Thienylmethyl, penta-Fluorobenzyl, 2-naphthylmethyl,4-biphenylmethyl, 9-Anthracenylmethyl, benzyl,(S)-(2-amino-3-phenyl)propyl, methyl, 2-aminoethyl and(S)-2-Aminopropyl; and B is selected from the group consisting of OH,NH₂, Trp-NH₂, 2-NaphthylAla-NH₂, Phe(penta-Fluoro)-NH₂, Ser(Bzl)-NH₂,Phe(4-NO₂)—NH₂, 3-PyridylAla-NH₂, Nva-NH₂, Lys-NH₂, Asp-NH₂, Ser-NH₂,His-NH₂, Tyr-NH₂, Phe-NH₂, L-Bip-NH₂, D-Ser-NH₂, Gly-OH, β-Ala-OH,GABA-OH and APA-OH.
 11. The isolated polypeptide of claim 1 wherein suchpolypeptide is a 10-mer to 15-mer and such polypeptide and binds to andactivates the GLP-1 receptor.
 12. An isolated polypeptide having asequence of Formula IA-X_(aa1)-X_(aa2)-X_(aa3)-X_(aa4)-X_(aa5)-X_(aa6)-X_(aa7)-X_(aa8)-X_(aa9)-Y-Z-B  Iwherein, X_(aa1-9) is a naturally or nonnaturally occurring amino acidresidue; Y and Z are amino acid residues; wherein one of thesubstitutions at the alpha-carbon atoms of Y and Z may eachindependently be substituted with a primary substituent group selectedfrom the group consisting of hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, saidprimary substituent optionally being substituted with a secondarysubstituent selected from a cycloalkyl, heterocyclyl, aryl or heteroarylgroup; any of said primary or secondary substituents may further besubstituted with one or more of, hydrogen, alkyl, cycloalkyl, arylalkyl,aryl, heterocycle, heteroaryl, alkenyl, alkynyl, halo, hydroxy,mercapto, nitro, cyano, amino, acylamino, azido, guanidino, amidino,carboxyl, carboxamido, carboxamido alkyl, formyl, acyl, carboxyl alkyl,alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, heterocycleoxy, acyloxy,mercapto, mercapto alkyl, mercaptoaryl, mercapto acyl, halo, cyano,nitro, azido, amino, guanidino alkyl, guanidino acyl, sulfonic,sulfonamido, alkyl sulfonyl, aryl sulfonyl or phosphonic group; wherein,the primary or secondary substitutents may optionally be bridged bycovalent bonds to form one or more fused cyclic or heterocyclic systemswith each other; wherein, the other substitution at the alpha-carbon ofY may be substituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl orcarboxyalkyl; wherein, the other substitution at the alpha-carbon of Zmay be substituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl orcarboxyalkyl; A and B are optionally present; wherein A is not present,and X_(aa1) is an R group, an R—C(O) (amide) group, a carbamate groupRO—C(O), a urea R₄R₅N—C(O), a sulfonamido R—SO₂, or a R₄R₅N—SO₂; whereinR is selected from the group consisting of hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl,arylalkyl, aryloxyalkyl, heteroarylalkyl, heteroaryloxyalkyl andheteroarylalkoxyalkyl; wherein R₄ and R₅ are each independently selectedfrom the group consisting of hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl,arylalkyl, aryloxyalkyl, heteroarylalkyl and heteroaryloxyalkyl; whereinB is present and B is OR₁, NR₁R₂, or an amino acid or peptide containingfrom 1 to 15 amino acid residues, terminating at the C-terminus as acarboxamide, substituted carboxamide, an ester, a free carboxylic acidor an amino-alcohol; and wherein R₁ and R₂ are independently chosen fromhydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl,heteroarylalkyl or heteroaryloxyalkyl.
 13. The isolated polypeptide ofclaim 12 wherein the substitutions upon the alpha-carbon atoms of Y andZ are selected from the group consisting of heteroarylarylmethyl,arylheteroarylmethyl or biphenylmethyl forming biphenylalanine residues,any of which is also optionally substituted with one or more, hydrogen,alkyl, cycloalkyl, arylalkyl, aryl, heterocyclyl, heteroaryl, alkenyl,alkynyl, halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido,guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl,acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy,heterocycleoxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl,mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl,guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl andphosphonic group.
 14. The isolated polypeptide of claim 12 wherein B isan amino acid or peptide containing 1 to about 10 amino acid residues.15. The isolated polypeptide of claim 14 wherein B is an amino acid orpeptide containing 1 to about 5 amino acid residues.
 16. The isolatedpolypeptide of claim 12 wherein X_(aa2) and X_(aa3) are N—H orN-alkylated amino acid residues.
 17. The isolated polypeptide of claim16 wherein X_(aa2) and X_(aa3) are N—H or N-methylated amino acidresidues.
 18. The isolated polypeptide of claim 12 wherein the othersubstitution at the alpha-carbon of Y is substituted with hydrogen,methyl or ethyl, and wherein the other substitution at the alpha-carbonof Z is substituted with hydrogen, methyl or ethyl.
 19. The isolatedpolypeptide of claim 12 wherein R, R₄ and R₅ are heteroarylalkyl orheterocycloalkyl, or R, R₄ and R₅ are cycloalkyl, cycloalkylalkyl,heterocycle, aryl, arylalkyl or aryloxyalkyl substituted with heteroarylor heterocycle.
 20. The isolated polypeptide of claim 12 wherein X_(aa2)is a naturally or nonnaturally occurring amino acid residue in which oneof the substitutions at the alpha-carbon is an alkyl or cycloalkyl wherethe alkyl group may optionally form a ring with the nitrogen of X_(aa2),and wherein the other substitution at the alpha-carbon is hydrogen oralkyl; X_(aa3) is a naturally or nonnaturally occurring amino acidresidue in which one of the substitutions at the alpha-carbon isselected from the group consisting of a carboxyalkyl, bis-carboxyalkyl,sulfonylalkyl, heteroalkyl and mercaptoalkyl; and wherein the othersubstitution at the alpha-carbon is hydrogen or alkyl; X_(aa4) is anaturally or nonnaturally occurring amino acid residue in which thealpha-carbon is not substituted, or in which one of the substitutions atthe alpha-carbon is selected from the group consisting of aminoalkyl,carboxyalkyl heteroarylalkyl and heterocycylalkyl; X_(aa5) is anaturally or nonnaturally occurring amino acid residue in which one ofthe substitutions at the alpha-carbon is an alkyl or hydroxyalkyl, andin which the other substitution at the alpha-carbon is hydrogen oralkyl; X_(aa6) is a naturally or nonnaturally occurring amino acidresidue in which one of the substitutions at the alpha-carbon isselected from the group consisting of alkyl, aryl, heteroaryl,heterocycle, cycloalkylalkyl, heterocyclealkyl, arylalkyl andheteroarylalkyl, and wherein the other substitution at the alpha-carbonis hydrogen or alkyl; X_(aa7) is a naturally or nonnaturally occurringamino acid residue in which one of the substitutions at the alpha-carbonis a hydroxylalkyl group; X_(aa8) is a naturally or nonnaturallyoccurring amino acid residue in which one of the substitutions at thealpha-carbon is selected from the group consisting of alkyl,hydroxylalkyl, heteroarylalkyl and carboxamidoalkyl, and in which theother substitution at the alpha-carbon is hydrogen or alkyl; and X_(aa9)is a naturally or nonnaturally occurring amino acid residue in which oneof the substitutions at alpha-carbon is selected from the groupconsisting of carboxylalkyl, bis-carboxylalkyl, carboxylaryl,sulfonylalkyl, carboxylamidoalkyl and heteroarylalkyl.
 21. The isolatedpolypeptide of claim 20 wherein X_(aa2) is an amino acid residueselected from the group consisting of L-Ala, D-Ala, L-Pro, Gly, D-Ser,D-Asn, L-N-Methyl-Ala, D-N-Methyl-Ala, L-4-ThioPro, L-Pro(t-4-OH),L-2-Pip, L-2-Azt, Aib, S— or R-Iva and Acc₃; X_(aa3) is an amino acidresidue selected from the group consisting of L-Glu, L-N-Methyl-Glu,L-Asp, D-Asp, L-His, L-Gla, L-Adp, L-Cys and L-4-ThiazolylAla; X_(aa4)is an amino acid residue selected from the group consisting of Gly,L-His, L-Lys and L-Asp; X_(aa5) is an amino acid residue selected fromthe group consisting of L-Thr, D-Thr, L-Nle, L-Met, L-Nva and L-Aoc;X_(aa6) is an amino acid residue selected from the group consisting ofL-Phe, L-Tyr, L-Tyr(Bzl), Tyr(3-NO₂), L-Nle, L-Trp, L-Phe(penta-Fluoro),D-Phe(penta-Fluoro), Phe(2-Fluoro), Phe(3-Fluoro), Phe(4-Fluoro),Phe(2,3-di-Fluoro), Phe(3,4-di-Fluoro), Phe(3,5-di-Fluoro),L-Phe(2,6-di-Fluoro), Phe(3,4,5-tri-Fluoro), Phe(2-Iodo), Phe(2-OH),Phe(2-OMethyl), Phe(3-OMethyl), Phe(3-Cyano), Phe(2-Chloro), Phe(2-NH₂),Phe(3-NH₂), Phe(4-NH₂), Phe(4-NO₂), Phe(4-Methyl), Phe(4-Allyl),Phe(n-butyl), Phe(4-Cyclohexyl), Phe(4-Cyclohexyloxy), Phe(4-Phenyloxy),2-NaphthylAla, 2-PyridylAla, L-4-ThiazolylAla, L-2-Thi, L-α-Me-Phe,D-α-Me-Phe, L-α-Et-Phe, D-α-Et-Phe, L-α-Me-Phe(2-Fluoro),D-α-Me-Phe(2-Fluoro), L-α-Me-Phe(2,3-di-Fluoro),D-α-Me-Phe(2,3-di-Fluoro), L-α-Me-Phe(2,6-di-Fluoro),D-α-Me-Phe(2,6-di-Fluoro), L-α-Me-Phe(penta-Fluoro) andD-α-Me-Phe(penta-Fluoro); X_(aa7) is an amino acid residue selected fromthe group consisting of L-Thr, D-Thr, L-Ser and L-hSer; X_(aa8) is anamino acid residue selected from the group consisting of L-Ser, L-hSer,L-His, L-Asn and L-α-Me-Ser; and X_(aa9) is an amino acid residueselected from the group consisting of L-Asp, L-Glu, L-Gla, L-Adp, L-Asnand L-His.
 22. The isolated polypeptide of claim 12 wherein Y isselected from the group consisting of L-Bip, D-Bip, L-Bip(2-Me),D-Bip(2-Me), L-Bip(2′-Me), L-Bip(2-Et), D-Bip(2-Et), L-Bip(3-Et),L-Bip(4-Et), L-Bip(2-n-Propyl), L-Bip(2-n-Propyl, 4-OMe),L-Bip(2-n-Propyl,2′-Me), L-Bip(3-Me), L-Bip(4-Me), L-Bip(2,3-di-Me),L-Bip(2,4-di-Me), L-Bip(2,6-di-Me), L-Bip(2,4-di-Et), L-Bip(2-Me,2′-Me), L-Bip(2-Et, 2′-Me), L-Bip(2-Et, 2′-Et), L-Bip(2-Me,4-OMe),L-Bip(2-Et,4-OMe), D-Bip(2-Et,4-OMe), L-Bip(3-OMe), L-Bip(4-OMe),L-Bip(2,4,6-tri-Me), L-Bip(2,3-di-OMe), L-Bip(2,4-di-OMe),L-Bip(2,5-di-OMe), L-Bip(3,4-di-OMe), L-Bip(2-Et,4,5-di-OMe),L-Bip(3,4-Methylene-di-oxy), L-Bip(2-Et, 4,5-Methylene-di-oxy),L-Bip(2-CH₂OH, 4-OMe), L-Bip(2-Ac), L-Bip(3-NH-Ac), L-Bip(4-NH-Ac),L-Bip(2,3-di-Chloro), L-Bip(2,4-di-Chloro), L-Bip(2,5-di-Chloro),L-Bip(3,4-di-Chloro), L-Bip(4-Fluoro), L-Bip(3,4-di-Fluoro),L-Bip(2,5-di-Fluoro), L-Bip(3-n-Propyl), L-Bip(4-n-Propyl),L-Bip(2-iso-Propyl), L-Bip(3-iso-Propyl), L-Bip(4-iso-Propyl),L-Bip(4-tert-Butyl), L-Bip(3-Phenyl), L-Bip(2-Chloro), L-Bip(3-Chloro),L-Bip(2-Fluoro), L-Bip(3-Fluoro), L-Bip(2-CF₃), L-Bip(3-CF₃),L-Bip(4-CF₃), L-Bip(3-NO₂), L-Bip(3-OCF₃), L-Bip(4-OCF₃), L-Bip(2-OEt),L-Bip(3-OEt), L-Bip(4-OEt), L-Bip(4-SMe), L-Bip(2-OH), L-Bip(3-OH),L-Bip(4-OH), L-Bip(2-CH₂—COOH), L-Bip(3-CH₂—COOH), L-Bip(4-CH₂—COOH),L-Bip(2-CH₂—NH₂), L-Bip(3-CH₂—NH₂), L-Bip(4-CH₂—NH₂), L-Bip(2-CH₂—OH),L-Bip(3-CH₂—OH), L-Bip(4-CH₂—OH), L-Phe[4-(1-propargyl)],L-Phe[4-(1-propenyl)], L-Phe[4-n-Butyl], L-Phe[4-Cyclohexyl],Phe(4-Phenyloxy), L-Phe(penta-Fluoro),L-2-(9,10-Dihydrophenanthrenyl)-Ala, 4-(2-Benzo(b)furan)-Phe,4-(4-Dibenzofuran)-Phe, 4-(4-Phenoxathiin)-Phe,4-(2-Benzo(b)thiophene)-Phe, 4-(3-thiophene)-Phe, 4-(3-Quinoline)-Phe,4-(2-Naphthyl)-Phe, 4-(1-Naphthyl)-Phe,4-(4-(3,5-dimethylisoxazole))-Phe, 4-(2,4-dimethoxypyrimidine)-Phe,homoPhe, Tyr(Bzl), Phe(3,4-di-Chloro), Phe(4-Iodo), 2-Naphthyl-Ala,L-α-Me-Bip and D-α-Me-Bip; Z is selected from the group consisting ofL-Bip, D-Bip, L-Bip(2-Me), D-Bip(2-Me), L-Bip(2′-Me), L-Bip(2-Et),D-Bip(2-Et), L-Bip(3-Me), L-Bip(4-Me), L-Bip(3-OMe), L-Bip(4-OMe),L-Bip(4-Et), L-Bip(2-n-Propyl,2′-Me), L-Bip(2,4-di-Me), L-Bip(2-Me,2′-Me), L-Bip(2-Me,4-OMe), L-Bip(2-Et,4-OMe), D-Bip(2-Et,4-OMe),L-Bip(2,6-di-Me), L-Bip(2,4,6-tri-Me), L-Bip(2,3,4,5,-tetra-Me),L-Bip(3,4-di-OMe), L-Bip(2,5-di-OMe), L-Bip(3,4-Methylene-di-oxy),L-Bip(3-NH-Ac), L-Bip(2-iso-Propyl), L-Bip(4-iso-Propyl),L-Bip(2-Phenyl), L-Bip(4-Phenyl), L-Bip(2-Fluoro), L-Bip(4-CF₃),L-Bip(4-OCF₃), L-Bip(2-OEt), L-Bip(4-OEt), L-Bip(4-SMe),L-Bip(2-CH₂—COOH), D-Bip(2-CH₂—COOH), L-Bip(2′-CH₂—COOH),L-Bip(3-CH₂—COOH), L-Bip(4-CH₂—COOH), L-Bip(2-CH₂—NH₂),L-Bip(3-CH₂—NH₂), L-Bip(4-CH₂—NH₂), L-Bip(2-CH₂—OH), L-Bip(3-CH₂—OH),L-Bip(4-CH₂—OH), L-Phe(3-Phenyl), L-Phe[4-n-Butyl], L-Phe[4-Cyclohexyl],Phe(4-Phenyloxy), L-Phe(penta-Fluoro),L-2-(9,10-Dihydrophenanthrenyl)-Ala, 4-(3-Pyridyl)-Phe,4-(2-Naphthyl)-Phe, 4-(1-Naphthyl)-Phe, 2-Naphthyl-Ala, 2-Fluorenyl-Ala,L-α-Me-Bip, D-α-Me-Bip, L-Phe(4-NO₂) and L-Phe(4-Iodo); and B isselected from the group consisting of OH, NH₂, Trp-NH₂,2-NaphthylAla-NH₂, Phe(penta-Fluoro)-NH₂, Ser(Bzl)-NH₂, Phe(4-NO₂)—NH₂,3-PyridylAla-NH₂, Nva-NH₂, Lys-NH₂, Asp-NH₂, Ser-NH₂, His-NH₂, Tyr-NH₂,Phe-NH₂, L-Bip-NH₂, D-Ser-NH₂, Gly-OH, 1-Ala-OH, GABA-OH and APA-OH. 23.The isolated polypeptide of claim 12 wherein such polypeptide is a10-mer to 15-mer and such polypeptide and binds to and activates theGLP-1 receptor.
 24. An isolated polypeptide having a sequence of FormulaIA-X_(aa1)-X_(aa2)-X_(aa3)-X_(aa4)-X_(aa5)-X_(aa6)-X_(aa7)-X_(aa8)-X_(aa9)-Y-Z-B  Iwherein, X_(aa1-9) is a naturally or nonnaturally occurring amino acidresidue; Y is an amino acid residue; wherein one of the substitutions atthe alpha-carbon atom of Y may independently be substituted with aprimary substituent group selected from the group consisting ofhydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl,arylalkyl and heteroarylalkyl, said primary substituent optionally beingsubstituted with a secondary substituent selected from a cycloalkyl,heterocyclyl, aryl or heteroaryl group; any of said primary or secondarysubstituents may further be substituted with one or more of, hydrogen,alkyl, cycloalkyl, arylalkyl, aryl, heterocyclyl, heteroaryl, alkenyl,alkynyl, halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido,guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl,acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy,heterocyclyloxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl,mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl,guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl orphosphonic group; wherein, the primary or secondary substitutents mayoptionally be bridged by covalent bonds to form one or more fused cyclicor heterocyclic systems with each other; wherein, the other substitutionat the alpha-carbon of Y may be substituted with hydrogen, alkyl,aminoalkyl, hydroxyalkyl or carboxyalkyl; A and B are optionallypresent; wherein A is present and A is hydrogen, an amino acid orpeptide containing from about 1 to about 15 amino acid residues, an Rgroup, an R—C(O) (amide) group, a carbamate group RO—C(O), a ureaR₄R₅N—C(O), a sulfonamido R—SO₂ or a R₄R₅N—SO₂; wherein R is selectedfrom the group consisting of hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, heteroaryl,arylalkyl, aryloxyalkyl, heteroarylalkyl and heteroaryloxyalkyl; whereinR₄ and R₅ are each independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle,heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl,heteroarylalkyl and heteroaryloxyalky; wherein the alpha-amino group ofX_(aa1) is substituted with a hydrogen or an alkyl group, said alkylgroup may optionally form a ring with A; wherein B is not present and Zis OR₁, NR₁R₂ or an amino-alcohol; and wherein R₁ and R₂ areindependently chosen from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,heterocycle, heterocycloalkyl, aryl, heteroaryl, arylalkyl,aryloxyalkyl, heteroarylalkyl or heteroaryloxyalkyl.
 25. The isolatedpolypeptide of claim 24 wherein the substitutions upon the alpha-carbonatoms of Y are selected from the group consisting ofheteroarylarylmethyl, arylheteroarylmethyl or biphenylmethyl formingbiphenylalanine residues, any of which is also optionally substitutedwith one or more, hydrogen, alkyl, cycloalkyl, arylalkyl, aryl,heterocyclyl, heteroaryl, alkenyl, alkynyl, halo, hydroxy, mercapto,nitro, cyano, amino, acylamino, azido, guanidino, amidino, carboxyl,carboxamido, carboxamido alkyl, formyl, acyl, carboxyl alkyl, alkoxy,aryloxy, arylalkyloxy, heteroaryloxy, heterocycleoxy, acyloxy, mercapto,mercapto alkyl, mercaptoaryl, mercapto acyl, halo, cyano, nitro, azido,amino, guanidino alkyl, guanidino acyl, sulfonic, sulfonamido, alkylsulfonyl, aryl sulfonyl and phosphonic group.
 26. The isolatedpolypeptide of claim 24 wherein B is an amino acid or peptide containing1 to about 10 amino acid residues.
 27. The isolated polypeptide of claim26 wherein B is an amino acid or peptide containing 1 to about 5 aminoacid residues.
 28. The isolated polypeptide of claim 24 wherein X_(aa1),X_(aa2) and X_(aa3) are N—H or N-alkylated amino acid residues.
 29. Theisolated polypeptide of claim 24 wherein X_(aa1), X_(aa2) and X_(aa3)are N—H or N-methylated amino acid residues.
 30. The isolatedpolypeptide of claim 24 wherein the other substitution at thealpha-carbon of Y is substituted with hydrogen, methyl or ethyl.
 31. Theisolated polypeptide of claim 24 wherein X_(aa1) is naturally ornonnaturally occurring amino acid residue in which one of thesubstitutions at the alpha-carbon is a primary substituent selected fromthe group consisting of heterocyclylalkyl, heteroaryl, heteroarylalkyl,and arylalkyl, said primary substituent optionally being substitutedwith secondary substituent selected from heteroaryl or heterocyclyl, andwherein the other substitution at the alpha-carbon is hydrogen or alkyl;X_(aa2) is naturally or nonnaturally occurring amino acid residue inwhich one of the substitutions at the alpha-carbon is an alkyl orcycloalkyl where the alkyl group may optionally form a ring with thenitrogen of X_(aa2), and wherein the other substitution at thealpha-carbon is hydrogen or alkyl; X_(aa3) is a naturally ornonnaturally occurring amino acid residue in which one of thesubstitutions at the alpha-carbon is selected from the group consistingof a carboxyalkyl, bis-carboxyalkyl, sulfonylalkyl, heteroalkyl andmercaptoalkyl, and wherein the other substitution at the alpha-carbon ishydrogen or alkyl; X_(aa4) is a naturally or nonnaturally occurringamino acid residue in which the alpha-carbon is not substituted, or inwhich one of the substitutions at the alpha-carbon is selected from thegroup consisting of aminoalkyl, carboxyalkyl heteroarylalkyl andheterocycylalkyl; X_(aa5) is a naturally or nonnaturally occurring aminoacid residue in which one of the substitutions at the alpha-carbon is analkyl or hydroxyalkyl, and wherein the other substitution at thealpha-carbon is hydrogen or alkyl; X_(aa6) is a naturally ornonnaturally occurring amino acid residue in which one of thesubstitutions at the alpha-carbon is selected from the group consistingof alkyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl,heterocyclealkyl, arylalkyl and heteroarylalkyl group, and wherein theother substitution at the alpha-carbon is hydrogen or alkyl; X_(aa7) isa naturally or nonnaturally occurring amino acid residue in which one ofthe substitutions at the alpha-carbon is a hydroxylalkyl group; X_(aa8)is a naturally or nonnaturally occurring amino acid residue in which oneof the substitutions at the alpha-carbon is selected from the groupconsisting of alkyl, hydroxylalkyl, heteroarylalkyl andcarboxamidoalkyl, and wherein the other substitution at the alpha-carbonis hydrogen or alkyl; X_(aa9) is a naturally or nonnaturally occurringamino acid residue in which one of the substitutions at alpha-carbon isselected from the group consisting of carboxylalkyl, bis-carboxylalkyl,carboxylaryl, sulfonylalkyl, carboxylamidoalkyl and heteroarylalkyl; andwherein A is hydrogen, an amino acid or peptide containing from about 1to about 5 amino acid residues, an R group, an R—C(O) (amide) group, acarbamate group RO—C(O), a urea R₄R₅N—C(O), a sulfonamido R—SO₂ or aR₄R₅N—SO₂.
 32. The isolated polypeptide of claim 24 wherein, X_(aa1) isan amino acid residue selected from the group consisting of L-His,D-His, L-N-Methyl-His, D-N-Methyl-His, L-4-ThiazolylAla andD-4-ThiazolylAla; X_(aa2) is an amino acid residue selected from thegroup consisting of L-Ala, D-Ala, L-Pro, Gly, D-Ser, D-Asn,L-N-Methyl-Ala, D-N-Methyl-Ala, L-4-ThioPro, L-Pro(t-4-OH), L-2-Pip,L-2-Azt, Aib, S- or R-Iva and Acc₃; X_(aa3) is an amino acid residueselected from the group consisting of L-Glu, L-N-Methyl-Glu, L-Asp,D-Asp, L-His, L-Gla, L-Adp, L-Cys and L-4-ThiazolylAla; X_(aa4) is anamino acid residue selected from the group consisting of Gly, L-His,L-Lys and L-Asp; X_(aa5) is an amino acid residue selected from thegroup consisting of L-Thr, D-Thr, L-Nle, L-Met, L-Nva and L-Aoc; X_(aa6)is an amino acid residue selected from the group consisting of L-Phe,L-Tyr, L-Tyr(Bzl), Tyr(3-NO₂), L-Nle, L-Trp, L-Phe(penta-Fluoro),D-Phe(penta-Fluoro), Phe(2-Fluoro), Phe(3-Fluoro), Phe(4-Fluoro),Phe(2,3-di-Fluoro), Phe(3,4-di-Fluoro), Phe(3,5-di-Fluoro),L-Phe(2,6-di-Fluoro), Phe(3,4,5-tri-Fluoro), Phe(2-Iodo), Phe(2-OH),Phe(2-OMethyl), Phe(3-OMethyl), Phe(3-Cyano), Phe(2-Chloro), Phe(2-NH₂),Phe(3-NH₂), Phe(4-NH₂), Phe(4-NO₂), Phe(4-Methyl), Phe(4-Allyl),Phe(n-butyl), Phe(4-Cyclohexyl), Phe(4-Cyclohexyloxy), Phe(4-Phenyloxy),2-NaphthylAla, 2-PyridylAla, L-4-ThiazolylAla, L-2-Thi, L-α-Me-Phe,D-α-Me-Phe, L-α-Et-Phe, D-α-Et-Phe, L-α-Me-Phe(2-Fluoro),D-α-Me-Phe(2-Fluoro), L-α-Me-Phe(2,3-di-Fluoro),D-α-Me-Phe(2,3-di-Fluoro), L-α-Me-Phe(2,6-di-Fluoro),D-α-Me-Phe(2,6-di-Fluoro), L-α-Me-Phe(penta-Fluoro) andD-α-Me-Phe(penta-Fluoro); X_(aa7) is an amino acid residue selected fromthe group consisting of L-Thr, D-Thr, L-Ser and L-hSer; X_(aa8) is anamino acid residue selected from the group consisting of L-Ser, L-hSer,L-His, L-Asn and L-α-Me-Ser; and X_(aa9) is an amino acid residueselected from the group consisting of L-Asp, L-Glu, L-Gla, L-Adp, L-Asnand L-His.
 33. The isolated polypeptide of claim 24 wherein Y isselected from the group consisting of L-Bip, D-Bip, L-Bip(2-Me),D-Bip(2-Me), L-Bip(2′-Me), L-Bip(2-Et), D-Bip(2-Et), L-Bip(3-Et),L-Bip(4-Et), L-Bip(2-n-Propyl), L-Bip(2-n-Propyl, 4-OMe),L-Bip(2-n-Propyl,2′-Me), L-Bip(3-Me), L-Bip(4-Me), L-Bip(2,3-di-Me),L-Bip(2,4-di-Me), L-Bip(2,6-di-Me), L-Bip(2,4-di-Et), L-Bip(2-Me,2′-Me), L-Bip(2-Et, 2′-Me), L-Bip(2-Et, 2′-Et), L-Bip(2-Me,4-OMe),L-Bip(2-Et,4-OMe), D-Bip(2-Et, 4-OMe), L-Bip(3-OMe), L-Bip(4-OMe),L-Bip(2,4,6-tri-Me), L-Bip(2,3-di-OMe), L-Bip(2,4-di-OMe),L-Bip(2,5-di-OMe), L-Bip(3,4-di-OMe), L-Bip(2-Et,4,5-di-OMe),L-Bip(3,4-Methylene-di-oxy), L-Bip(2-Et, 4,5-Methylene-di-oxy),L-Bip(2-CH₂OH, 4-OMe), L-Bip(2-Ac), L-Bip(3-NH-Ac), L-Bip(4-NH-Ac),L-Bip(2,3-di-Chloro), L-Bip(2,4-di-Chloro), L-Bip(2,5-di-Chloro),L-Bip(3,4-di-Chloro), L-Bip(4-Fluoro), L-Bip(3,4-di-Fluoro),L-Bip(2,5-di-Fluoro), L-Bip(3-n-Propyl), L-Bip(4-n-Propyl),L-Bip(2-iso-Propyl), L-Bip(3-iso-Propyl), L-Bip(4-iso-Propyl),L-Bip(4-tert-Butyl), L-Bip(3-Phenyl), L-Bip(2-Chloro), L-Bip(3-Chloro),L-Bip(2-Fluoro), L-Bip(3-Fluoro), L-Bip(2-CF₃), L-Bip(3-CF₃),L-Bip(4-CF₃), L-Bip(3-NO₂), L-Bip(3-OCF₃), L-Bip(4-OCF₃), L-Bip(2-OEt),L-Bip(3-OEt), L-Bip(4-OEt), L-Bip(4-SMe), L-Bip(2-OH), L-Bip(3-OH),L-Bip(4-OH), L-Bip(2-CH₂—COOH), L-Bip(3-CH₂—COOH), L-Bip(4-CH₂—COOH),L-Bip(2-CH₂—NH₂), L-Bip(3-CH₂—NH₂), L-Bip(4-CH₂—NH₂), L-Bip(2-CH₂—OH),L-Bip(3-CH₂—OH), L-Bip(4-CH₂—OH), L-Phe[4-(1-propargyl)],L-Phe[4-(1-propenyl)], L-Phe[4-n-Butyl], L-Phe[4-Cyclohexyl],Phe(4-Phenyloxy), L-Phe(penta-Fluoro),L-2-(9,10-Dihydrophenanthrenyl)-Ala, 4-(2-Benzo(b)furan)-Phe,4-(4-Dibenzofuran)-Phe, 4-(4-Phenoxathiin)-Phe,4-(2-Benzo(b)thiophene)-Phe, 4-(3-thiophene)-Phe, 4-(3-Quinoline)-Phe,4-(2-Naphthyl)-Phe, 4-(1-Naphthyl)-Phe,4-(4-(3,5-dimethylisoxazole))-Phe, 4-(2,4-dimethoxypyrimidine)-Phe,homoPhe, Tyr(Bzl), Phe(3,4-di-Chloro), Phe(4-Iodo), 2-Naphthyl-Ala,L-α-Me-Bip and D-α-Me-Bip; and A is selected from the group consistingof H, Acetyl, β-Ala, Ahx, Gly, Asp, Glu, Phe, Lys, Nva, Asn, Arg, Ser,Thr, Val, Trp, Tyr, Caprolactam, L-Bip, L-Ser(Bzl), 3-PyridylAla,Phe(4-Me), Phe(penta-Fluoro), 4-Methylbenzyl, 4-Fluorobenzyl, n-propyl,n-hexyl, cyclohexylmethyl, 6-hydroxypentyl, 2-Thienylmethyl,3-Thienylmethyl, penta-Fluorobenzyl, 2-naphthylmethyl, 4-biphenylmethyl,9-Anthracenylmethyl, benzyl, (S)-(2-amino-3-phenyl)propyl, methyl,2-aminoethyl and (S)-2-Aminopropyl.
 34. An isolated polypeptide of claim24 wherein said polypeptide is a 10-mer to 15-mer and said polypeptidebinds and activates a GLP-1 receptor.
 35. An isolated polypeptide havinga sequence of Formula IA-X_(aa1)-X_(aa2)-X_(aa3)-X_(aa4)-X_(aa5)-X_(aa6)-X_(aa7)-X_(aa8)-X_(aa9)-Y-Z-B  Iwherein, X_(aa1-9) is a naturally or nonnaturally occurring amino acidresidue; Y is an amino acid residue; wherein one of the substitutions atthe alpha-carbon atom of Y may each independently be substituted with aprimary substituent group selected from the group consisting ofhydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl,arylalkyl and heteroarylalkyl, said primary substituent optionally beingsubstituted with a primary or secondary substituent selected from acycloalkyl, heterocycle, aryl or heteroaryl group; any of said secondarysubstituents may further be substituted with one or more of, hydrogen,alkyl, cycloalkyl, arylalkyl, aryl, heterocycle, heteroaryl, alkenyl,alkynyl, halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido,guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl,acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy,heterocycleoxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl,mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl,guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl orphosphonic group; wherein, the primary or secondary substitutents mayoptionally be bridged by covalent bonds to form one or more fused cyclicor heterocyclic systems with each other; wherein, the other substitutionat the alpha-carbon of Y may be substituted with hydrogen, alkyl,aminoalkyl, hydroxyalkyl or carboxyalkyl; A and B are optionallypresent; wherein A is not present, and X_(aa1) is an R group, an R—C(O)(amide) group, a carbamate group RO—C(O), a urea R₄R₅N—C(O), asulfonamido R—SO₂ or a R₄R₅N—SO₂; wherein R is selected from the groupconsisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle,heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl,heteroarylalkyl, heteroaryloxyalkyl and heteroarylalkoxyalkyl; whereinR₄ and R₅ are each independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle,heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl,heteroarylalkyl and heteroaryloxyalky; wherein B is not present and Z isOR₁, NR₁R₂ or an amino-alcohol; and wherein R₁ and R₂ are independentlychosen from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle,heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl,heteroarylalkyl or heteroaryloxyalkyl.
 36. The isolated polypeptide ofclaim 35 wherein the substitutions upon the alpha-carbon atoms of Y areselected from the group consisting of heteroarylarylmethyl,arylheteroarylmethyl or biphenylmethyl forming biphenylalanine residues,any of which is also optionally substituted with one or more, hydrogen,alkyl, cycloalkyl, arylalkyl, aryl, heterocycle, heteroaryl, alkenyl,alkynyl, halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido,guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl,acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy,heterocycleoxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl,mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl,guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl andphosphonic group.
 37. The isolated polypeptide of claim 35 whereinX_(aa2) and X_(aa3) are N—H or N-alkylated amino acids residues.
 38. Theisolated polypeptide of claim 37 wherein X_(aa2) and X_(aa3) are N—H orN-methylated amino acid residues.
 39. The isolated polypeptide of claim35 wherein the other substitution at the alpha-carbon of Y issubstituted with methyl or ethyl.
 40. The isolated polypeptide of claim35 wherein R, R₄ and R₅ are heteroarylalkyl or heterocycloalkyl, or R,R₄ and R₅ are cycloalkyl, cycloalkylalkyl, heterocycle, aryl, arylalkylor aryloxyalkyl substituted with heteroaryl or heterocycle.
 41. Theisolated polypeptide of claim 35 wherein X_(aa2) is naturally ornonnaturally occurring amino acid residue in which one of thesubstitutions at the alpha-carbon is an alkyl or cycloalkyl where thealkyl group may optionally form a ring with the nitrogen of X_(aa2), andwherein the other substitution at the alpha-carbon is hydrogen or alkyl;X_(aa3) is a naturally or nonnaturally occurring amino acid residue inwhich one of the substitutions at the alpha-carbon is selected from thegroup consisting of a carboxyalkyl, bis-carboxyalkyl, sulfonylalkyl,heteroalkyl and mercaptoalkyl, and wherein the other substitution at thealpha-carbon is hydrogen or alkyl; X_(aa4) is a naturally ornonnaturally occurring amino acid residue in which the alpha-carbon isnot substituted, or in which one of the substitutions at thealpha-carbon is selected from the group consisting of aminoalkyl,carboxyalkyl heteroarylalkyl and heterocycylalkyl; X_(aa5) is anaturally or nonnaturally occurring amino acid residue in which one ofthe substitutions at the alpha-carbon is an alkyl or hydroxyalkyl, andwherein the other substitution at the alpha-carbon is hydrogen or alkyl;X_(aa6) is a naturally or nonnaturally occurring amino acid residue inwhich one of the substitutions at the alpha-carbon is selected from thegroup consisting of alkyl, aryl, heteroaryl, heterocycle,cycloalkylalkyl, heterocyclealkyl, arylalkyl and heteroarylalkyl, andwherein the other substitution at the alpha-carbon is hydrogen or alkyl;X_(aa7) is a naturally or nonnaturally occurring amino acid residue inwhich one of the substitutions at the alpha-carbon is a hydroxylalkylgroup; X_(aa8) is a naturally or nonnaturally occurring amino acidresidue in which one of the substitutions at the alpha-carbon isselected from the group consisting of alkyl, hydroxylalkyl,heteroarylalkyl and carboxamidoalkyl, and wherein the other substitutionat the alpha-carbon is hydrogen or alkyl; and X_(aa9) is a naturally ornonnaturally occurring amino acid residue in which one of thesubstitutions at alpha-carbon is selected from the group consisting ofcarboxylalkyl, bis-carboxylalkyl, carboxylaryl, sulfonylalkyl,carboxylamidoalkyl and heteroarylalkyl.
 42. The isolated polypeptide ofclaim 41 wherein X_(aa2) is an amino acid residue selected from thegroup consisting of L-Ala, D-Ala, L-Pro, Gly, D-Ser, D-Asn,L-N-Methyl-Ala, D-N-Methyl-Ala, L-4-ThioPro, L-Pro(t-4-OH), L-2-Pip,L-2-Azt, Aib, S— or R-Iva and Acc₃; X_(aa3) is an amino acid residueselected from the group consisting of L-Glu, L-N-Methyl-Glu, L-Asp,D-Asp, L-His, L-Gla, L-Adp, L-Cys and L-4-ThiazolylAla; X_(aa4) is anamino acid residue selected from the group consisting of Gly, L-His,L-Lys and L-Asp; X_(aa5) is an amino acid residue selected from thegroup consisting of L-Thr, D-Thr, L-Nle, L-Met, L-Nva and L-Aoc; X_(aa6)is an amino acid residue selected from the group consisting of L-Phe,L-Tyr, L-Tyr(Bzl), Tyr(3-NO₂), L-Nle, L-Trp, L-Phe(penta-Fluoro),D-Phe(penta-Fluoro), Phe(2-Fluoro), Phe(3-Fluoro), Phe(4-Fluoro),Phe(2,3-di-Fluoro), Phe(3,4-di-Fluoro), Phe(3,5-di-Fluoro),L-Phe(2,6-di-Fluoro), Phe(3,4,5-tri-Fluoro), Phe(2-Iodo), Phe(2-OH),Phe(2-OMethyl), Phe(3-OMethyl), Phe(3-Cyano), Phe(2-Chloro), Phe(2-NH₂),Phe(3-NH₂), Phe(4-NH₂), Phe(4-NO₂), Phe(4-Methyl), Phe(4-Allyl),Phe(n-butyl), Phe(4-Cyclohexyl), Phe(4-Cyclohexyloxy), Phe(4-Phenyloxy),2-NaphthylAla, 2-PyridylAla, L-4-ThiazolylAla, L-2-Thi, L-α-Me-Phe,D-α-Me-Phe, L-α-Et-Phe, D-α-Et-Phe, L-α-Me-Phe(2-Fluoro),D-α-Me-Phe(2-Fluoro), L-α-Me-Phe(2,3-di-Fluoro),D-α-Me-Phe(2,3-di-Fluoro), L-α-Me-Phe(2,6-di-Fluoro),D-α-Me-Phe(2,6-di-Fluoro), L-α-Me-Phe(penta-Fluoro) andD-α-Me-Phe(penta-Fluoro); X_(aa7) is an amino acid residue selected fromthe group consisting of L-Thr, D-Thr, L-Ser and L-hSer; X_(aa8) is anamino acid residue selected from the group consisting of L-Ser, L-hSer,L-His, L-Asn and L-α-Me-Ser; and X_(aa9) is an amino acid residueselected from the group consisting of L-Asp, L-Glu, L-Gla, L-Adp, L-Asnand L-His.
 43. The isolated polypeptide of claim 35 wherein Y isselected from the group consisting of L-Bip, D-Bip, L-Bip(2-Me),D-Bip(2-Me), L-Bip(2′-Me), L-Bip(2-Et), D-Bip(2-Et), L-Bip(3-Et),L-Bip(4-Et), L-Bip(2-n-Propyl), L-Bip(2-n-Propyl, 4-OMe),L-Bip(2-n-Propyl,2′-Me), L-Bip(3-Me), L-Bip(4-Me), L-Bip(2,3-di-Me),L-Bip(2,4-di-Me), L-Bip(2,6-di-Me), L-Bip(2,4-di-Et), L-Bip(2-Me,2′-Me), L-Bip(2-Et, 2′-Me), L-Bip(2-Et, 2′-Et), L-Bip(2-Me,4-OMe),L-Bip(2-Et,4-OMe), D-Bip(2-Et,4-OMe), L-Bip(3-OMe), L-Bip(4-OMe),L-Bip(2,4,6-tri-Me), L-Bip(2,3-di-OMe), L-Bip(2,4-di-OMe),L-Bip(2,5-di-OMe), L-Bip(3,4-di-OMe), L-Bip(2-Et,4,5-di-OMe),L-Bip(3,4-Methylene-di-oxy), L-Bip(2-Et, 4,5-Methylene-di-oxy),L-Bip(2-CH₂OH, 4-OMe), L-Bip(2-Ac), L-Bip(3-NH-Ac), L-Bip(4-NH-Ac),L-Bip(2,3-di-Chloro), L-Bip(2,4-di-Chloro), L-Bip(2,5-di-Chloro),L-Bip(3,4-di-Chloro), L-Bip(4-Fluoro), L-Bip(3,4-di-Fluoro),L-Bip(2,5-di-Fluoro), L-Bip(3-n-Propyl), L-Bip(4-n-Propyl),L-Bip(2-iso-Propyl), L-Bip(3-iso-Propyl), L-Bip(4-iso-Propyl),L-Bip(4-tert-Butyl), L-Bip(3-Phenyl), L-Bip(2-Chloro), L-Bip(3-Chloro),L-Bip(2-Fluoro), L-Bip(3-Fluoro), L-Bip(2-CF₃), L-Bip(3-CF₃),L-Bip(4-CF₃), L-Bip(3-NO₂), L-Bip(3-OCF₃), L-Bip(4-OCF₃), L-Bip(2-OEt),L-Bip(3-OEt), L-Bip(4-OEt), L-Bip(4-SMe), L-Bip(2-OH), L-Bip(3-OH),L-Bip(4-OH), L-Bip(2-CH₂—COOH), L-Bip(3-CH₂—COOH), L-Bip(4-CH₂—COOH),L-Bip(2-CH₂—NH₂), L-Bip(3-CH₂—NH₂), L-Bip(4-CH₂—NH₂), L-Bip(2-CH₂—OH),L-Bip(3-CH₂—OH), L-Bip(4-CH₂—OH), L-Phe[4-(1-propargyl)],L-Phe[4-(1-propenyl)], L-Phe[4-n-Butyl], L-Phe[4-Cyclohexyl],Phe(4-Phenyloxy), L-Phe(penta-Fluoro),L-2-(9,10-Dihydrophenanthrenyl)-Ala, 4-(2-Benzo(b)furan)-Phe,4-(4-Dibenzofuran)-Phe, 4-(4-Phenoxathiin)-Phe,4-(2-Benzo(b)thiophene)-Phe, 4-(3-thiophene)-Phe, 4-(3-Quinoline)-Phe,4-(2-Naphthyl)-Phe, 4-(1-Naphthyl)-Phe,4-(4-(3,5-dimethylisoxazole))-Phe, 4-(2,4-dimethoxypyrimidine)-Phe,homoPhe, Tyr(Bzl), Phe(3,4-di-Chloro), Phe(4-Iodo), 2-Naphthyl-Ala,L-α-Me-Bip and D-α-Me-Bip.
 44. The isolated polypeptide of claim 35wherein such polypeptide is a 10-mer to 15-mer and such polypeptide andbinds to and activates the GLP-1 receptor.
 45. A method of making apolypeptide recognized by the family of B G-protein coupled receptorswherein the polypeptide mimics the activity of a polypeptide receptoragonist, said polypeptide having the formula

the method comprising replacing an address sequence of the polypeptidereceptor agonist with Y and Z, wherein Y and Z are amino acid residues;wherein one of the substitutions at the alpha-carbon atoms of Y and Zmay each independently be substituted with a primary substituent groupselected from the group consisting of hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl,heterocyclyl said primary substituent optionally being substituted witha secondary substituent selected from a cycloalkyl, heterocyclyl, arylor heteroaryl group; any of said primary or secondary substituents mayfurther be substituted with one or more of, hydrogen, alkyl, cycloalkyl,arylalkyl, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl, halo,hydroxy, mercapto, nitro, cyano, amino, acylamino, azido, guanidino,amidino, carboxyl, carboxamido, carboxamido alkyl, formyl, acyl,carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy,heterocycleoxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl,mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl,guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl orphosphonic group; wherein, the primary or secondary substitutents mayoptionally be bridged by covalent bonds to form one or more fused cyclicor heterocyclic systems with each other; wherein, the other substitutionat the alpha-carbon of Y may be substituted with hydrogen, alkyl,aminoalkyl, hydroxyalkyl or carboxyalkyl; wherein, the othersubstitution at the alpha-carbon of Z may be substituted with hydrogen,alkyl, aminoalkyl, hydroxyalkyl or carboxyalkyl; and whereinX_(aa1)-X_(aan) is a message sequence capable of inducing receptormediated signal transduction.
 46. The method of claim 45 wherein thepolypeptide mimics the activity of an endogenous polypeptide receptoragonist.
 47. The method of claim 45 wherein the polypeptide receptoragonist is GLP-1.
 48. The method of claim 45 further comprisingreplacing the message sequence of the polypeptide receptor agonist witha variant message sequence capable of inducing receptor mediated signaltransduction.
 49. A pharmaceutical composition comprising a polypeptideof claim 1 and a pharmaceutically acceptable carrier therefor.
 50. Apharmaceutical combination comprising a polypeptide of claim 49 and atleast one therapeutic agent selected from the group consisting of anantidiabetic agent, an anti-obesity agent, an anti-hypertensive agent,an anti-atherosclerotic agent and a lipid-lowering agent.
 51. Thecombination of claim 50 wherein the antidiabetic agent is at least oneagent selected from the group consisting of a biguanide, a GPR119agonist, a sulfonyl urea, a glucosidase inhibitor, a PPAR γ agonist, aPPAR α/γ dual agonist, an aP2 inhibitor, a DP4 inhibitor, an insulinsensitizer, a glucagon-like peptide-1 (GLP-1), insulin and ameglitinide.
 52. The combination of claim 51 wherein the antidiabeticagent is at least one agent selected from the group consisting ofmetformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide,gliclazide, acarbose, miglitol, pioglitazone, troglitazone,rosiglitazone, insulin, farglitizar, isaglitazone, reglitizar,balaglitazone,(Z)-1,4-bis{4-[(3,5-Dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy}but-2-ene, rivoglitazone, rafaegron, repaglinide, nateglinide,(S)-2-benzyl-4-oxo-4-(cis-perhydroisoindol-2-yl)butyric acid calciumsalt, tesaglitizar, L-phenylalanine,N-[(1Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]-4-[3-(5-methyl-2-phenyl-4-oxazolyl)propyl],benzamide,5-[(2,4-dioxo-5-thiazolidinyl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl],exenatide, 8-37-glucagon-like peptide I(human)-N-[3-(1H-imidazol-4-yl)-1-oxopropyl]-26-L-arginine-34-[N6-(1-oxooctyl)-L-lysine],and vildagliptin.
 53. The combination of claim 50 wherein theanti-obesity agent is at least one agent selected from the groupconsisting of a beta 3 adrenergic agonist, a lipase inhibitor, aserotonin reuptake inhibitor, a dopamine reuptake inhibitor, a serotoninand dopamine reuptake inhibitor, a thyroid receptor beta compound, andan anorectic agent.
 54. The combination of claim 53 wherein theanti-obesity agent is at least one agent selected from the groupconsisting of orlistat, cetilistat, rafabregon,N-[4-[2-[[(2S)-3-[(6-amino-3-pyridinyl)oxy]-2-hydroxypropyl]amino]ethyl]phenyl]-4-(1-methylethyl)-benzenesulfonamide,sibutramine, topiramate, axokine, dexamphetamine, phentermine,phenylpropanolamine and mazindol.
 55. The combination of claim 50wherein the lipid lowering agent is at least one agent selected from thegroup consisting of an MTP inhibitor, cholesterol ester transferprotein, an HMG CoA reductase inhibitor, a squalene synthetaseinhibitor, a fibric acid derivative, an upregulator of LDL receptoractivity, a lipoxygenase inhibitor, or an ACAT inhibitor.
 56. Thecombination of claim 55 wherein the lipid lowering agent is at least oneagent selected from the group consisting of pravastatin, lovastatin,simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin,visastatin, fenofibrate, gemfibrozil, clofibrate, avasimibe,N-[2,6-bis(1-methylethyl)phenyl]-2-(tetradecylthio)-acetamide,3-(13-hydroxy-10-oxotetradecyl)-5,7-dimethoxy-1(3H)-isobenzofuranone,torcetrapib, and (3 alpha,4 alpha,5 alpha)-4-(2-propenylcholestan-3-ol).57. A method for treating or delaying the progression or onset ofdiabetes, diabetic retinopathy, diabetic neuropathy, diabeticnephropathy, wound healing, insulin resistance, hyperglycemia,hyperinsulinemia, Syndrome X, diabetic complications, elevated bloodlevels of free fatty acids or glycerol, hyperlipidemia, obesity,hypertriglyceridemia, atherosclerosis or hypertension, which comprisesadministering to a mammalian species in need of treatment atherapeutically effective amount of a polypeptide of claim
 1. 58. Themethod of claim 57 further comprising administering, a therapeuticallyeffective amount of at least one additional therapeutic agent selectedfrom the group consisting of an antidiabetic agent, an anti-obesityagent, a anti-hypertensive agent, an anti-atherosclerotic agent and alipid-lowering agent.
 59. A method for treating or delaying theprogression or onset of diabetes or a diabetes-related conditioncomprising administering a therapeutically effective amount of anisolated polypeptide comprising the amino acid sequence of SEQ ID NO:456.
 60. The method of claim 59 wherein said isolated peptide isadministered as a pharmaceutical composition.
 61. The method of claim 59wherein said diabetes-related condition is a condition selected from thegroup consisting of diabetic retinopathy, diabetic neuropathy, diabeticnephropathy, wound healing, insulin resistance, hyperglycemia,hyperinsulinemia, Syndrome X, diabetic complications, elevated bloodlevels of free fatty acids or glycerol, hyperlipidemia, obesity,hypertriglyceridemia, atherosclerosis and hypertension.
 62. The methodof claim 59 further comprising administering, a therapeuticallyeffective amount of at least one additional therapeutic agent selectedfrom the group consisting of an antidiabetic agent, an anti-obesityagent, a anti-hypertensive agent, an anti-atherosclerotic agent and alipid-lowering agent.
 63. The method of claim 62 wherein theantidiabetic agent is at least one agent selected from the groupconsisting of a biguanide, a sulfonyl urea, a glucosidase inhibitor, aperoxisome proliferator-activated receptor (PPAR) γ agonist, a PPAR α/γdual agonist, an adipocyte lipid binding protein (aP2) inhibitor, adipeptidyl peptidase 4 (DP4) inhibitor, an insulin sensitizer, aglucagon-like peptide-1 (GLP-1), insulin and a meglitinide.
 64. Themethod of claim 63 wherein the antidiabetic agent is at least one agentselected from the group consisting of metformin, glyburide, glimepiride,glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol,pioglitazone, troglitazone, rosiglitazone, insulin, farglitizar,isaglitazone, reglitizar, balaglitazone,(Z)-1,4-bis{4-[(3,5-Dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy}but-2-ene, rivoglitazone, rafaegron, repaglinide, nateglinide,(S)-2-benzyl-4-oxo-4-(cis-perhydroisoindol-2-yl)butyric acid calciumsalt, tesaglitizar, L-phenylalanine,N-[(1Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]-4-[3-(5-methyl-2-phenyl-4-oxazolyl)propyl],5-[(2,4-dioxo-5-thiazolidinyl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]-benzamide,exenatide, 8-37-glucagon-like peptide I(human)-N-[3-(1H-imidazol-4-yl)-1-oxopropyl]-26-L-arginine-34-[N6-(1-oxooctyl)-L-lysine],and vildagliptin.
 65. The method of claim 62 wherein the anti-obesityagent is at least one agent selected from the group consisting of a beta3 adrenergic agonist, a lipase inhibitor, a serotonin reuptakeinhibitor, a dopamine reuptake inhibitor, a serotonin and dopaminereuptake inhibitor, a thyroid receptor beta compound, and an anorecticagent.
 66. The method of claim 65 wherein the anti-obesity agent is atleast one agent selected from the group consisting of orlistat,cetilistat, rafabregon,N-[4-[2-[[(2S)-3-[(6-amino-3-pyridinyl)oxy]-2-hydroxypropyl]amino]ethyl]phenyl]-4-(1-methylethyl)-benzenesulfonamide,sibutramine, topiramate, axokine, dexamphetamine, phentermine,phenylpropanolamine and mazindol.
 67. The method of claim 62 wherein thelipid lowering agent is at least one agent selected from the groupconsisting of a microsomal triglyceride transfer protein (MTP)inhibitor, cholesterol ester transfer protein, ahydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitor, asqualene synthetase inhibitor, a fibric acid derivative, an upregulatorof low-density lipoprotein (LDL) receptor activity, a lipoxygenaseinhibitor, or an acyl coenzyme A-cholesterol acyltransferase (ACAT)inhibitor.
 68. The method of claim 67 wherein the lipid lowering agentis at least one agent selected from the group consisting of pravastatin,lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin,nisvastatin, visastatin, fenofibrate, gemfibrozil, clofibrate,avasimibe,N-[2,6-bis(1-methylethyl)phenyl]-2-(tetradecylthio)-acetamide,3-(13-hydroxy-10-oxotetradecyl)-5,7-dimethoxy-1(3H)-isobenzofuranone,torcetrapib, and (3 alpha,4 alpha,5 alpha)-4-(2-propenylcholestan-3-ol).69. The method of claim 59 wherein the isolated polypeptide is selectedfrom the group consisting of SEQ ID NOs: 1-23, 25-27, 31-32, 34-140,142-145, 148, 150, 153-155, 157-160, 162, 164, 166, 168-227, 231-234,236, 238-271, 276-290, 292, 294-295, 274-455, and 457-517.
 70. A methodfor treating or delaying the progression or onset of diabetes or adiabetes-related condition comprising administering a therapeuticallyeffective amount of an isolated polypeptide selected from the groupconsisting of SEQ ID NOs: 1-23, 25-27, 31-32, 34-140, 142-145, 148, 150,153-155, 157-160, 162, 164, 166, 168-227, 231-234, 236, 238-271,276-290, 292, 294-295, 274-455, and 457-517.
 71. An isolated polypeptidecomprising the amino acid sequence of SEQ ID NO: 518 wherein saidpolypeptide binds and activates a GLP-1 receptor.
 72. A pharmaceuticalcomposition comprising a polypeptide of claim 71, and a pharmaceuticallyacceptable carrier.
 73. A pharmaceutical combination comprising apolypeptide of claim 71 and at least one therapeutic agent selected fromthe group consisting of an antidiabetic agent, an anti-obesity agent, ananti-hypertensive agent, an anti-atherosclerotic agent and alipid-lowering agent.
 74. The combination of claim 73 wherein theantidiabetic agent is at least one agent selected from the groupconsisting of a biguanide, a sulfonyl urea, a glucosidase inhibitor, aperoxisome proliferator-activated receptor (PPAR) γ agonist, a PPAR α/γdual agonist, an adipocyte lipid binding protein (aP2) inhibitor, adipeptidyl peptidase 4 (DP4) inhibitor, an insulin sensitizer, aglucagon-like peptide-1 (GLP-1), insulin and a meglitinide.
 75. Thecombination of claim 74 wherein the antidiabetic agent is at least oneagent selected from the group consisting of metformin, glyburide,glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose,miglitol, pioglitazone, troglitazone, rosiglitazone, insulin,farglitizar, isaglitazone, reglitizar, balaglitazone,(Z)-1,4-bis{4-[(3,5-Dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy}but-2-ene, rivoglitazone, rafaegron, repaglinide, nateglinide,(S)-2-benzyl-4-oxo-4-(cis-perhydroisoindol-2-yl)butyric acid calciumsalt, tesaglitizar, L-phenylalanine,N-[(1Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]-4-[3-(5-methyl-2-phenyl-4-oxazolyl)propyl],5-[(2,4-dioxo-5-thiazolidinyl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]-benzamide,exenatide, 8-37-glucagon-like peptide I(human)-N-[3-(1H-imidazol-4-yl)-1-oxopropyl]-26-L-arginine-34-[N6-(1-oxooctyl)-L-lysine],and vildagliptin.
 76. The combination of claim 73 wherein theanti-obesity agent is at least one agent selected from the groupconsisting of a beta 3 adrenergic agonist, a lipase inhibitor, aserotonin reuptake inhibitor, a dopamine reuptake inhibitor, a serotoninand dopamine reuptake inhibitor, a thyroid receptor beta compound, andan anorectic agent.
 77. The combination of claim 76 wherein theanti-obesity agent is at least one agent selected from the groupconsisting of orlistat, cetilistat, rafabregon,N-[4-[2-[[(2S)-3-[(6-amino-3-pyridinyl)oxy]-2-hydroxypropyl]amino]ethyl]phenyl]-4-(1-methylethyl)-benzenesulfonamide,sibutramine, topiramate, axokine, dexamphetamine, phentermine,phenylpropanolamine and mazindol.
 78. The combination of claim 73wherein the lipid lowering agent is at least one agent selected from thegroup consisting of a microsomal triglyceride transfer protein (MTP)inhibitor, cholesterol ester transfer protein, ahydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitor, asqualene synthetase inhibitor, a fibric acid derivative, an upregulatorof low-density lipoprotein (LDL) receptor activity, a lipoxygenaseinhibitor, or an acyl coenzyme A-cholesterol acyltransferase (ACAT)inhibitor.
 79. The combination of claim 78 wherein the lipid loweringagent is at least one agent selected from the group consisting ofpravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin,fluvastatin, nisvastatin, visastatin, fenofibrate, gemfibrozil,clofibrate, avasimibe,N-[2,6-bis(1-methylethyl)phenyl]-2-(tetradecylthio)-acetamide,3-(13-hydroxy-10-oxotetradecyl)-5,7-dimethoxy-1(3H)-isobenzofuranone,torcetrapib, and (3 alpha,4 alpha,5 alpha)-4-(2-propenylcholestan-3-ol).80. The isolated polypeptide of claim 71 wherein said polypeptide isselected from the group consisting of SEQ ID NOs: 24, 28, 29, 30, 33,141, 146, 147, 149, 151, 152, 156, 161, 163, 165, 167, 228, 229, 230,235, 237, 272, 273, 274, 275, 291, 293 and
 296. 81. A pharmaceuticalcomposition comprising a polypeptide of claim 80, and a pharmaceuticallyacceptable carrier.
 82. A pharmaceutical combination comprising apolypeptide of claim 80 and at least one therapeutic agent selected fromthe group consisting of an antidiabetic agent, an anti-obesity agent, ananti-hypertensive agent, an anti-atherosclerotic agent and alipid-lowering agent.
 83. The combination of claim 82 wherein theantidiabetic agent is at least one agent selected from the groupconsisting of a biguanide, a sulfonyl urea, a glucosidase inhibitor, aPPAR γ agonist, a PPAR α/γ dual agonist, an aP2 inhibitor, a DP4inhibitor, an insulin sensitizer, a GLP-1, insulin and a meglitinide.84. The combination of claim 83 wherein the antidiabetic agent is atleast one agent selected from the group consisting of metformin,glyburide, glimepiride, glipyride, glipizide, chlorpropamide,gliclazide, acarbose, miglitol, pioglitazone, troglitazone,rosiglitazone, insulin, farglitizar, isaglitazone, reglitizar,balaglitazone,(Z)-1,4-bis{4-[(3,5-Dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy}but-2-ene, rivoglitazone, rafaegron, repaglinide, nateglinide,(S)-2-benzyl-4-oxo-4-(cis-perhydroisoindol-2-yl)butyric acid calciumsalt, tesaglitizar, L-phenylalanine,N-[(1Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]-4-[3-(5-methyl-2-phenyl-4-oxazolyl)propyl],5-[(2,4-dioxo-5-thiazolidinyl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]-benzamide,exenatide, 8-37-glucagon-like peptide I(human)-N-[3-(1H-imidazol-4-yl)-1-oxopropyl]-26-L-arginine-34-[N6-(1-oxooctyl)-L-lysine],and vildagliptin.
 85. The combination of claim 82 wherein theanti-obesity agent is at least one agent selected from the groupconsisting of a beta 3 adrenergic agonist, a lipase inhibitor, aserotonin reuptake inhibitor, a dopamine reuptake inhibitor, a serotoninand dopamine reuptake inhibitor, a thyroid receptor beta compound, andan anorectic agent.
 86. The combination of claim 85 wherein theanti-obesity agent is at least one agent selected from the groupconsisting of orlistat, cetilistat, rafabregon,N-[4-[2-[[(2S)-3-[(6-amino-3-pyridinyl)oxy]-2-hydroxypropyl]amino]ethyl]phenyl]-4-(1-methylethyl)-benzenesulfonamide,sibutramine, topiramate, axokine, dexamphetamine, phentermine,phenylpropanolamine and mazindol.
 87. The combination of claim 82wherein the lipid lowering agent is at least one agent selected from thegroup consisting of an MTP inhibitor, cholesterol ester transferprotein, an HMG CoA reductase inhibitor, a squalene synthetaseinhibitor, a fibric acid derivative, an upregulator of LDL receptoractivity, a lipoxygenase inhibitor, or an ACAT inhibitor.
 88. Thecombination of claim 87 wherein the lipid lowering agent is at least oneagent selected from the group consisting of pravastatin, lovastatin,simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin,visastatin, fenofibrate, gemfibrozil, clofibrate, avasimibe,N-[2,6-bis(1-methylethyl)phenyl]-2-(tetradecylthio)-acetamide,3-(13-hydroxy-10-oxotetradecyl)-5,7-dimethoxy-1(3H)-isobenzofuranone,torcetrapib, and (3 alpha,4 alpha,5 alpha)-4-(2-propenylcholestan-3-ol).89. An isolated polypeptide selected from the group consisting of: SEQID Nos: 24, 28, 29, 30, 33, 141, 146, 147, 149, 151, 152, 156, 161, 163,165, 167, 228, 229, 230, 235, 237, 272, 273, 274, 275, 291, 293 and 296.90. A pharmaceutical composition comprising a polypeptide of claim 89,and a pharmaceutically acceptable carrier.
 91. A pharmaceuticalcombination comprising a polypeptide of claim 89 and at least onetherapeutic agent selected from the group consisting of an antidiabeticagent, an anti-obesity agent, an anti-hypertensive agent, ananti-atherosclerotic agent and a lipid-lowering agent.
 92. Thecombination of claim 91 wherein the antidiabetic agent is at least oneagent selected from the group consisting of a biguanide, a sulfonylurea, a glucosidase inhibitor, a PPAR γ agonist, a PPAR α/γ dualagonist, an aP2 inhibitor, a DP4 inhibitor, an insulin sensitizer, aglucagon-like peptide-1 (GLP-1), insulin and a meglitinide.
 93. Thecombination of claim 92 wherein the antidiabetic agent is at least oneagent selected from the group consisting of metformin, glyburide,glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose,miglitol, pioglitazone, troglitazone, rosiglitazone, insulin,farglitizar, isaglitazone, reglitizar, balaglitazone,(Z)-1,4-bis{4-[(3,5-Dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy}but-2-ene, rivoglitazone, rafaegron, repaglinide, nateglinide,(S)-2-benzyl-4-oxo-4-(cis-perhydroisoindol-2-yl)butyric acid calciumsalt, tesaglitizar, L-phenylalanine,N-[(1Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]-4-[3-(5-methyl-2-phenyl-4-oxazolyl)propyl],benzamide,5-[(2,4-dioxo-5-thiazolidinyl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl],exenatide, 8-37-glucagon-like peptide I(human)-N-[3-(1H-imidazol-4-yl)-1-oxopropyl]-26-L-arginine-34-[N6-(1-oxooctyl)-L-lysine],and vildagliptin.
 94. The combination of claim 91 wherein theanti-obesity agent is at least one agent selected from the groupconsisting of a beta 3 adrenergic agonist, a lipase inhibitor, aserotonin reuptake inhibitor, a dopamine reuptake inhibitor, a serotoninand dopamine reuptake inhibitor, a thyroid receptor beta compound, andan anorectic agent.
 95. The combination of claim 94 wherein theanti-obesity agent is at least one agent selected from the groupconsisting of orlistat, cetilistat, rafabregon,N-[4-[2-[[(2S)-3-[(6-amino-3-pyridinyl)oxy]-2-hydroxypropyl]amino]ethyl]phenyl]-4-(1-methylethyl)-benzenesulfonamide,sibutramine, topiramate, axokine, dexamphetamine, phentermine,phenylpropanolamine and mazindol.
 96. The combination of claim 92wherein the lipid lowering agent is at least one agent selected from thegroup consisting of an MTP inhibitor, cholesterol ester transferprotein, an HMG CoA reductase inhibitor, a squalene synthetaseinhibitor, a fibric acid derivative, an upregulator of LDL receptoractivity, a lipoxygenase inhibitor, or an ACAT inhibitor.
 97. Thecombination of claim 96 wherein the lipid lowering agent is at least oneagent selected from the group consisting of pravastatin, lovastatin,simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin,visastatin, fenofibrate, gemfibrozil, clofibrate, avasimibe,N-[2,6-bis(1-methylethyl)phenyl]-2-(tetradecylthio)-acetamide,3-(13-hydroxy-10-oxotetradecyl)-5,7-dimethoxy-1(3H)-isobenzofuranone,torcetrapib, and (3 alpha,4 alpha,5 alpha)-4-(2-propenylcholestan-3-ol).